Mitogen-Activated Protein Kinase 10
G-Protein-Coupled Receptor Kinases
Receptors, Adrenergic, beta-2
G-Protein-Coupled Receptor Kinase 3
G-Protein-Coupled Receptor Kinase 2
G-Protein-Coupled Receptor Kinase 1
Receptors, Formyl Peptide
G-Protein-Coupled Receptor Kinase 5
Amino Acid Sequence
Molecular Sequence Data
Photoreceptor Cells, Vertebrate
Sequence Homology, Amino Acid
Fluorescent Antibody Technique, Indirect
Recombinant Fusion Proteins
Proto-Oncogene Proteins c-mdm2
Protein Structure, Tertiary
Green Fluorescent Proteins
Amino Acid Motifs
Receptors, Cell Surface
Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. (1/1016)Internalization of agonist-activated G protein-coupled receptors is mediated by non-visual arrestins, which also bind to clathrin and are therefore thought to act as adaptors in the endocytosis process. Phosphoinositides have been implicated in the regulation of intracellular receptor trafficking, and are known to bind to other coat components including AP-2, AP180 and COPI coatomer. Given these observations, we explored the possibility that phosphoinositides play a role in arrestin's function as an adaptor. High-affinity binding sites for phosphoinositides in beta-arrestin (arrestin2) and arrestin3 (beta-arrestin2) were identified, and dissimilar effects of phosphoinositide and inositol phosphate on arrestin interactions with clathrin and receptor were characterized. Alteration of three basic residues in arrestin3 abolished phosphoinositide binding with complete retention of clathrin and receptor binding. Unlike native protein, upon agonist activation, this mutant arrestin3 expressed in COS1 cells neither supported beta2-adrenergic receptor internalization nor did it concentrate in coated pits, although it was recruited to the plasma membrane. These findings indicate that phosphoinositide binding plays a critical regulatory role in delivery of the receptor-arrestin complex to coated pits, perhaps by providing, with activated receptor, a multi-point attachment of arrestin to the plasma membrane. (+info)
Targeted construction of phosphorylation-independent beta-arrestin mutants with constitutive activity in cells. (2/1016)Arrestin proteins play a key role in the desensitization of G protein-coupled receptors (GPCRs). Recently we proposed a molecular mechanism whereby arrestin preferentially binds to the activated and phosphorylated form of its cognate GPCR. To test the model, we introduced two different types of mutations into beta-arrestin that were expected to disrupt two crucial elements that make beta-arrestin binding to receptors phosphorylation-dependent. We found that two beta-arrestin mutants (Arg169 --> Glu and Asp383 --> Ter) (Ter, stop codon) are indeed "constitutively active." In vitro these mutants bind to the agonist-activated beta2-adrenergic receptor (beta2AR) regardless of its phosphorylation status. When expressed in Xenopus oocytes these beta-arrestin mutants effectively desensitize beta2AR in a phosphorylation-independent manner. Constitutively active beta-arrestin mutants also effectively desensitize delta opioid receptor (DOR) and restore the agonist-induced desensitization of a truncated DOR lacking the critical G protein-coupled receptor kinase (GRK) phosphorylation sites. The kinetics of the desensitization induced by phosphorylation-independent mutants in the absence of receptor phosphorylation appears identical to that induced by wild type beta-arrestin + GRK3. Either of the mutations could have occurred naturally and made receptor kinases redundant, raising the question of why a more complex two-step mechanism (receptor phosphorylation followed by arrestin binding) is universally used. (+info)
Real-time visualization of the cellular redistribution of G protein-coupled receptor kinase 2 and beta-arrestin 2 during homologous desensitization of the substance P receptor. (3/1016)The substance P receptor (SPR) is a G protein-coupled receptor (GPCR) that plays a key role in pain regulation. The SPR desensitizes in the continued presence of agonist, presumably via mechanisms that implicate G protein-coupled receptor kinases (GRKs) and beta-arrestins. The temporal relationship of these proposed biochemical events has never been established for any GPCR other than rhodopsin beyond the resolution provided by biochemical assays. We investigate the real-time activation and desensitization of the human SPR in live HEK293 cells using green fluorescent protein conjugates of protein kinase C, GRK2, and beta-arrestin 2. The translocation of protein kinase C betaII-green fluorescent protein to and from the plasma membrane in response to substance P indicates that the human SPR becomes activated within seconds of agonist exposure, and the response desensitizes within 30 s. This desensitization process coincides with a redistribution of GRK2 from the cytosol to the plasma membrane, followed by a robust redistribution of beta-arrestin 2 and a profound change in cell morphology that occurs after 1 min of SPR stimulation. These data establish a role for GRKs and beta-arrestins in homologous desensitization of the SPR and provide the first visual and temporal resolution of the sequence of events underlying homologous desensitization of a GPCR in living cells. (+info)
Internalization of the TXA2 receptor alpha and beta isoforms. Role of the differentially spliced cooh terminus in agonist-promoted receptor internalization. (4/1016)Thromboxane A2 (TXA2) potently stimulates platelet aggregation and smooth muscle constriction and is thought to play a role in myocardial infarction, atherosclerosis, and bronchial asthma. The TXA2 receptor (TXA2R) is a member of the G protein-coupled receptor family and is found as two alternatively spliced isoforms, alpha (343 residues) and beta (407 residues), which share the first 328 residues. In the present report, we demonstrate by enzyme-linked immunosorbent assay and immunofluorescence microscopy that the TXA2Rbeta, but not the TXA2Ralpha, undergoes agonist-induced internalization when expressed in HEK293 cells as well as several other cell types. Various dominant negative mutants were used to demonstrate that the internalization of the TXA2Rbeta is dynamin-, GRK-, and arrestin-dependent in HEK293 cells, suggesting the involvement of receptor phosphorylation and clathrin-coated pits in this process. Interestingly, the agonist-stimulated internalization of both the alpha and beta isoforms, but not of a mutant truncated after residue 328, can be promoted by overexpression of arrestin-3, identifying the C-tails of both receptors as necessary in arrestin-3 interaction. Simultaneous mutation of two dileucine motifs in the C-tail of TXA2Rbeta did not affect agonist-promoted internalization. Analysis of various C-tail deletion mutants revealed that a region between residues 355 and 366 of the TXA2Rbeta is essential for agonist-promoted internalization. These data demonstrate that alternative splicing of the TXA2R plays a critical role in regulating arrestin binding and subsequent receptor internalization. (+info)
The absence of a direct correlation between the loss of [D-Ala2, MePhe4,Gly5-ol]Enkephalin inhibition of adenylyl cyclase activity and agonist-induced mu-opioid receptor phosphorylation. (5/1016)Chronic activation of the mu-opioid receptor (MOR1TAG) results in the loss of agonist response that has been attributed to desensitization and down-regulation of the receptor. It has been suggested that opioid receptor phosphorylation is the mechanism by which this desensitization and down-regulation occurs. When MOR1TAG was stably expressed in both neuroblastoma neuro2A and human embryonic kidney HEK293 cells, the opioid agonist [D-Ala2,MePhe4, Gly5-ol]enkephalin (DAMGO) induced a time- and concentration-dependent phosphorylation of the receptor, in both cell lines, that could be reversed by the antagonist naloxone. Protein kinase C can phosphorylate the receptor, but is not involved in DAMGO-induced MOR1TAG phosphorylation. The rapid rate of receptor phosphorylation, occurring within minutes, did not correlate with the rate of the loss of agonist-mediated inhibition of adenylyl cyclase, which occurs in hours. This lack of correlation between receptor phosphorylation and the loss of response was further demonstrated when receptor phosphorylation was increased by either calyculin A or overexpression of the G-protein receptor kinases. Calyculin A increased the magnitude of MOR1TAG phosphorylation without altering the DAMGO-induced loss of the adenylyl cyclase response. Similarly, when mu- and delta-opioid (DOR1TAG) receptors were expressed in the same system, overexpression of beta-adrenergic receptor kinase 2 elevated agonist-induced phosphorylation for both receptors. However, in the same cell lines under the same conditions, overexpression of beta-adrenergic receptor kinase 2 and beta-arrestin 2 accelerated the rate of DPDPE- but not DAMGO-induced receptor desensitization. Thus, these data show that phosphorylation of MOR1TAG is not an obligatory event for the DAMGO-induced loss in the adenylyl cyclase regulation by the receptor. (+info)
Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis. (6/1016)Beta2-Adrenergic and chemokine receptor antagonists delay the onset and reduce the severity of joint injury in rheumatoid arthritis. beta2-Adrenergic and chemokine receptors belong to the G-protein-coupled receptor family whose responsiveness is turned off by the G-protein-coupled receptor kinase family (GRK-1 to 6). GRKs phosphorylate receptors in an agonist-dependent manner resulting in receptor/G-protein uncoupling via subsequent binding of arrestin proteins. We assessed the activity of GRKs in lymphocytes of rheumatoid arthritis (RA) patients by rhodopsin phosphorylation. We found a significant decrease in GRK activity in RA subjects that is mirrored by a decrease in GRK-2 protein expression. Moreover, GRK-6 protein expression is reduced in RA patients whereas GRK-5 protein levels were unchanged. In search of an underlying mechanism, we demonstrated that proinflammatory cytokines induce a decrease in GRK-2 protein levels in leukocytes from healthy donors. Since proinflammatory cytokines are abundantly expressed in RA, it may provide an explanation for the decrease in GRK-2 expression and activity in patients. No changes in beta2-adrenergic receptor number and Kd were detected. However, RA patients showed a significantly increased cAMP production and inhibition of TNF-alpha production by beta2-adrenergic stimulation, suggesting that reduced GRK activity is associated with increased sensitivity to beta2-adrenergic activation. (+info)
The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis. (7/1016)betaarrestins mediate the desensitization of the beta2-adrenergic receptor (beta2AR) and many other G protein-coupled receptors (GPCRs). Additionally, betaarrestins initiate the endocytosis of these receptors via clathrin coated-pits and interact directly with clathrin. Consequently, it has been proposed that betaarrestins serve as clathrin adaptors for the GPCR family by linking these receptors to clathrin lattices. AP-2, the heterotetrameric clathrin adaptor protein, has been demonstrated to mediate the internalization of many types of plasma membrane proteins other than GPCRs. AP-2 interacts with the clathrin heavy chain and cytoplasmic domains of receptors such as those for epidermal growth factor and transferrin. In the present study we demonstrate the formation of an agonist-induced multimeric complex containing a GPCR, betaarrestin 2, and the beta2-adaptin subunit of AP-2. beta2-Adaptin binds betaarrestin 2 in a yeast two-hybrid assay and coimmunoprecipitates with betaarrestins and beta2AR in an agonist-dependent manner in HEK-293 cells. Moreover, beta2-adaptin translocates from the cytosol to the plasma membrane in response to the beta2AR agonist isoproterenol and colocalizes with beta2AR in clathrin-coated pits. Finally, expression of betaarrestin 2 minigene constructs containing the beta2-adaptin interacting region inhibits beta2AR endocytosis. These findings point to a role for AP-2 in GPCR endocytosis, and they suggest that AP-2 functions as a clathrin adaptor for the endocytosis of diverse classes of membrane receptors. (+info)
Identification of NSF as a beta-arrestin1-binding protein. Implications for beta2-adrenergic receptor regulation. (8/1016)Previous studies have demonstrated that beta-arrestin1 serves to target G protein-coupled receptors for internalization via clathrin-coated pits and that its endocytic function is regulated by dephosphorylation at the plasma membrane. Using the yeast two-hybrid system, we have identified a novel beta-arrestin1-binding protein, NSF (N-ethylmaleimide-sensitive fusion protein), an ATPase essential for many intracellular transport reactions. We demonstrate that purified recombinant beta-arrestin1 and NSF interact in vitro and that these proteins can be coimmunoprecipitated from cells. beta-Arrestin1-NSF complex formation exhibits a conformational dependence with beta-arrestin1 preferentially interacting with the ATP bound form of NSF. In contrast to the beta-arrestin1-clathrin interaction, however, the phosphorylation state of beta-arrestin1 does not affect NSF binding. Functionally, overexpression of NSF in HEK 293 cells significantly enhances agonist-mediated beta2-adrenergic receptor (beta2-AR) internalization. Furthermore, when coexpressed with a beta-arrestin1 mutant (betaarr1S412D) that mimics a constitutively phosphorylated form of beta-arrestin1 and that acts as a dominant negative with regards to beta2-AR internalization, NSF rescues the betaarr1S412D-mediated inhibition of beta2-AR internalization. The demonstration of beta-arrestin1-NSF complex formation and the functional consequences of NSF overexpression suggest a hitherto unappreciated role for NSF in facilitating clathrin coat-mediated G protein-coupled receptor internalization. (+info)
Arrestins are a family of proteins that play a role in regulating the activity of G protein-coupled receptors (GPCRs) in the cell. They are named for their ability to "arrest" or stop the activity of GPCRs after they have been activated by a signaling molecule such as a hormone or neurotransmitter. When a GPCR is activated, it triggers a signaling cascade that can lead to a variety of cellular responses. Arrestins bind to the activated GPCR and prevent it from interacting with other signaling molecules, effectively turning off the signaling cascade. This allows the cell to quickly reset the receptor and prepare for the next signaling event. Arrestins also play a role in the internalization of GPCRs, which is the process by which the receptors are removed from the cell surface and transported to the cell's interior. This can help to regulate the availability of GPCRs on the cell surface and prevent overstimulation of the receptor. Arrestins are found in a variety of organisms, including humans, and are involved in a wide range of physiological processes, including vision, metabolism, and the immune response. They are also the targets of several drugs, including some used to treat conditions such as diabetes and obesity.
Arrestin is a protein that plays a role in regulating the activity of certain receptors in the cell. It is involved in the process of desensitization, which is the decrease in the responsiveness of a receptor to its ligand (the molecule that binds to the receptor and triggers a response). Arrestin helps to internalize and degrade receptors that have been activated by their ligands, which prevents them from continuing to respond to the ligand. This process is important for maintaining the proper functioning of cells and for preventing overstimulation of receptors. Arrestins are found in a variety of cells and are involved in regulating the activity of a number of different receptors, including those for hormones, neurotransmitters, and sensory stimuli.
Mitogen-Activated Protein Kinase 10 (MAPK10), also known as p38γ, is a protein kinase enzyme that plays a role in cellular signaling pathways. It is a member of the mitogen-activated protein kinase (MAPK) family, which is involved in regulating various cellular processes such as cell growth, differentiation, and apoptosis. MAPK10 is activated by various extracellular stimuli, including cytokines, growth factors, and stress signals. Once activated, it phosphorylates and regulates the activity of downstream target proteins, including transcription factors and other signaling molecules. In the medical field, MAPK10 has been implicated in various diseases and conditions, including cancer, inflammatory disorders, and neurodegenerative diseases. For example, dysregulation of MAPK10 signaling has been observed in several types of cancer, including breast, lung, and colon cancer, and may contribute to tumor growth and progression. Additionally, MAPK10 has been shown to play a role in the regulation of immune responses and may be involved in the pathogenesis of inflammatory disorders such as rheumatoid arthritis and psoriasis. Finally, MAPK10 has been implicated in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, and may contribute to the progression of these conditions by regulating the activity of proteins involved in neuronal function and survival.
G-protein-coupled receptor kinases (GRKs) are a family of enzymes that play a critical role in regulating the function of G-protein-coupled receptors (GPCRs) in the human body. GPCRs are a large group of cell surface receptors that are activated by a variety of extracellular signals, including hormones, neurotransmitters, and sensory stimuli. When a GPCR is activated, it triggers a signaling cascade that ultimately leads to a cellular response. GRKs are activated by phosphorylation, which allows them to bind to and phosphorylate activated GPCRs. This phosphorylation event leads to the internalization of the receptor from the cell surface, which in turn terminates the signaling cascade and desensitizes the receptor to further activation. This process is an important mechanism for regulating the activity of GPCRs and preventing overstimulation of the cell. GRKs are involved in a wide range of physiological processes, including vision, hearing, smell, taste, and the regulation of blood pressure, heart rate, and other cardiovascular functions. Mutations in GRK genes have been linked to a number of human diseases, including cardiovascular disease, diabetes, and certain types of cancer.
Rhodopsin is a protein found in the retina of the eye that is responsible for the process of vision in low light conditions. It is a type of photopigment that is sensitive to light in the short-wavelength region of the visible spectrum, which corresponds to blue and violet light. When light strikes the rhodopsin molecules, it causes a chemical change in the protein that triggers a series of events that ultimately leads to the transmission of visual information to the brain. Rhodopsin is essential for night vision and plays a critical role in the early stages of the visual process.
Receptors, Adrenergic, beta-2 (β2-adrenergic receptors) are a type of protein found on the surface of cells in the body that bind to and respond to the hormone adrenaline (also known as epinephrine). These receptors are part of the adrenergic receptor family, which also includes alpha-adrenergic receptors (α-adrenergic receptors). β2-adrenergic receptors are found in many different tissues throughout the body, including the lungs, heart, and blood vessels. When adrenaline binds to these receptors, it triggers a series of chemical reactions within the cell that can have a variety of effects, depending on the tissue type and the specific receptor subtype. In the lungs, activation of β2-adrenergic receptors can cause bronchodilation, which is the widening of the airways and can help to improve breathing. In the heart, activation of these receptors can increase heart rate and contractility, which can help to improve blood flow. In the blood vessels, activation of β2-adrenergic receptors can cause vasodilation, which is the widening of blood vessels and can help to lower blood pressure. β2-adrenergic receptors are also important in the body's response to stress. When the body is under stress, the adrenal gland releases adrenaline, which binds to these receptors and triggers the body's "fight or flight" response. This response can help the body to prepare for physical activity and to respond to potential threats. In the medical field, β2-adrenergic receptors are the target of many medications, including bronchodilators used to treat asthma and other respiratory conditions, and beta blockers used to treat high blood pressure and other cardiovascular conditions.
G-Protein-Coupled Receptor Kinase 3 (GRK3) is a protein that plays a role in regulating the activity of G-protein-coupled receptors (GPCRs) in the body. GPCRs are a large family of cell surface receptors that are activated by a variety of extracellular signals, such as hormones, neurotransmitters, and sensory stimuli. When a GPCR is activated, it triggers a cascade of intracellular events that ultimately lead to a cellular response. GRK3 is a type of protein kinase that phosphorylates activated GPCRs, which in turn leads to the internalization of the receptor and its degradation. This process is an important mechanism for regulating the activity of GPCRs and preventing overstimulation of the cell. Dysregulation of GRK3 activity has been implicated in a number of diseases, including cardiovascular disease, neurological disorders, and cancer.
Receptors, G-Protein-Coupled (GPCRs) are a large family of membrane proteins that play a crucial role in transmitting signals from the outside of a cell to the inside. They are found in almost all types of cells and are involved in a wide range of physiological processes, including sensory perception, neurotransmission, and hormone signaling. GPCRs are activated by a variety of molecules, including neurotransmitters, hormones, and sensory stimuli such as light, sound, and odor. When a molecule binds to a GPCR, it causes a conformational change in the protein that activates a G protein, a small molecule that acts as a molecular switch. The activated G protein then triggers a cascade of intracellular signaling events that ultimately lead to a cellular response. Because GPCRs are involved in so many different physiological processes, they are an important target for drug discovery. Many drugs, including those used to treat conditions such as hypertension, depression, and allergies, work by binding to specific GPCRs and modulating their activity.
G-Protein-Coupled Receptor Kinase 2 (GRK2) is a protein that plays a role in regulating the activity of G-protein-coupled receptors (GPCRs) in the human body. GPCRs are a large family of cell surface receptors that are activated by a variety of extracellular signals, such as hormones, neurotransmitters, and sensory stimuli. When a GPCR is activated, it triggers a cascade of intracellular signaling events that ultimately lead to changes in cell behavior. GRK2 is a type of protein kinase that phosphorylates activated GPCRs, which in turn leads to the internalization of the receptor from the cell surface. This process is an important mechanism for regulating the activity of GPCRs and preventing overstimulation of the cell. Dysregulation of GRK2 activity has been implicated in a number of diseases, including cardiovascular disease, diabetes, and certain types of cancer.
Dynamins are a family of GTPases that play important roles in various cellular processes, including endocytosis, exocytosis, vesicle trafficking, and intracellular signaling. They are characterized by their ability to hydrolyze GTP (guanosine triphosphate) and are involved in the regulation of membrane dynamics and the formation of vesicles. In the medical field, dynamins are of interest because they have been implicated in a number of diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's disease, as well as certain types of cancer.
G-Protein-Coupled Receptor Kinase 1 (GRK1) is a protein that plays a role in regulating the activity of G-protein-coupled receptors (GPCRs) in the human body. GPCRs are a large family of cell surface receptors that are activated by a variety of extracellular signals, such as hormones, neurotransmitters, and sensory stimuli. When a GPCR is activated, it triggers a cascade of intracellular events that ultimately lead to a cellular response. GRK1 is a member of a family of enzymes called G-protein-coupled receptor kinases (GRKs) that phosphorylate activated GPCRs, which in turn leads to the internalization and degradation of the receptor. This process helps to regulate the activity of GPCRs and prevent overstimulation of the cell. GRK1 has been implicated in a number of physiological processes, including vision, hearing, and the regulation of blood pressure. It has also been linked to a number of diseases, including cardiovascular disease, diabetes, and certain types of cancer.
Clathrin is a protein that plays a crucial role in the process of endocytosis, which is the process by which cells take in substances from their environment. Clathrin forms a lattice-like structure that surrounds and helps to shape the plasma membrane as it buds inward to form a vesicle. This vesicle then pinches off from the plasma membrane and is transported into the cell, where it can be processed and used by the cell. Clathrin is also involved in the transport of certain molecules within the cell, such as the transport of proteins from the Golgi apparatus to the plasma membrane. In the medical field, clathrin is often studied in relation to diseases such as cancer, where it has been implicated in the formation of abnormal blood vessels and the spread of cancer cells.
Receptors, Formyl Peptide are a type of protein receptors found on the surface of immune cells, such as neutrophils and macrophages. These receptors are activated by the presence of formylated peptides, which are a type of amino acid sequence found on the N-terminus of certain bacterial proteins. Activation of these receptors triggers a signaling cascade that leads to the recruitment and activation of immune cells at the site of infection, helping to mount an immune response against the invading bacteria.
G-Protein-Coupled Receptor Kinase 5 (GRK5) is a protein that plays a role in regulating the activity of G-protein-coupled receptors (GPCRs) in the body. GPCRs are a large family of cell surface receptors that are activated by a variety of extracellular signals, such as hormones, neurotransmitters, and sensory stimuli. When a GPCR is activated, it triggers a cascade of intracellular events that ultimately lead to a cellular response. GRK5 is a member of a family of enzymes called G-protein-coupled receptor kinases (GRKs) that phosphorylate activated GPCRs, which in turn leads to the internalization and degradation of the receptor. This process helps to regulate the activity of GPCRs and prevent overstimulation of the cell. GRK5 has been implicated in a number of physiological processes, including the regulation of cardiovascular function, the control of blood pressure, and the modulation of pain perception. It has also been linked to a number of diseases, including hypertension, heart failure, and chronic pain.
Eye proteins are proteins that are found in the eye and play important roles in maintaining the structure and function of the eye. These proteins can be found in various parts of the eye, including the cornea, lens, retina, and vitreous humor. Some examples of eye proteins include: 1. Collagen: This is a protein that provides strength and support to the cornea and lens. 2. Alpha-crystallin: This protein is found in the lens and helps to maintain its shape and transparency. 3. Rhodopsin: This protein is found in the retina and is responsible for vision in low light conditions. 4. Vitreous humor proteins: These proteins are found in the vitreous humor, a clear gel-like substance that fills the space between the lens and the retina. They help to maintain the shape of the eye and provide support to the retina. Disruptions in the production or function of these proteins can lead to various eye diseases and conditions, such as cataracts, glaucoma, and age-related macular degeneration. Therefore, understanding the structure and function of eye proteins is important for the development of effective treatments for these conditions.
Receptors, Muscarinic are a type of cell surface receptors that are activated by the neurotransmitter acetylcholine. They are found in various tissues throughout the body, including the heart, lungs, digestive system, and central nervous system. There are five subtypes of muscarinic receptors, designated M1 through M5, each with different properties and functions. Activation of muscarinic receptors can produce a wide range of effects, including contraction of smooth muscle, stimulation of glandular secretion, and modulation of neurotransmitter release. In the medical field, muscarinic receptors are important targets for the treatment of various conditions, including asthma, irritable bowel syndrome, and certain types of heart disease. Drugs that interact with muscarinic receptors are often referred to as muscarinic agonists or antagonists, depending on whether they stimulate or block the activity of the receptors.
GTP-binding proteins, also known as G proteins, are a family of proteins that play a crucial role in signal transduction in cells. They are involved in a wide range of cellular processes, including cell growth, differentiation, and metabolism. G proteins are composed of three subunits: an alpha subunit, a beta subunit, and a gamma subunit. The alpha subunit is the one that binds to guanosine triphosphate (GTP), a molecule that is involved in regulating the activity of the protein. When GTP binds to the alpha subunit, it causes a conformational change in the protein, which in turn activates or inhibits downstream signaling pathways. G proteins are activated by a variety of extracellular signals, such as hormones, neurotransmitters, and growth factors. Once activated, they can interact with other proteins in the cell, such as enzymes or ion channels, to transmit the signal and initiate a cellular response. G proteins are found in all eukaryotic cells and play a critical role in many physiological processes. They are also involved in a number of diseases, including cancer, neurological disorders, and cardiovascular diseases.
Phosphoproteins are proteins that have been modified by the addition of a phosphate group to one or more of their amino acid residues. This modification is known as phosphorylation, and it is a common post-translational modification that plays a critical role in regulating many cellular processes, including signal transduction, metabolism, and gene expression. Phosphoproteins are involved in a wide range of biological functions, including cell growth and division, cell migration and differentiation, and the regulation of gene expression. They are also involved in many diseases, including cancer, diabetes, and cardiovascular disease. Phosphoproteins can be detected and studied using a variety of techniques, including mass spectrometry, Western blotting, and immunoprecipitation. These techniques allow researchers to identify and quantify the phosphorylation status of specific proteins in cells and tissues, and to study the effects of changes in phosphorylation on protein function and cellular processes.
Recombinant fusion proteins are proteins that are produced by combining two or more genes in a single molecule. These proteins are typically created using genetic engineering techniques, such as recombinant DNA technology, to insert one or more genes into a host organism, such as bacteria or yeast, which then produces the fusion protein. Fusion proteins are often used in medical research and drug development because they can have unique properties that are not present in the individual proteins that make up the fusion. For example, a fusion protein might be designed to have increased stability, improved solubility, or enhanced targeting to specific cells or tissues. Recombinant fusion proteins have a wide range of applications in medicine, including as therapeutic agents, diagnostic tools, and research reagents. Some examples of recombinant fusion proteins used in medicine include antibodies, growth factors, and cytokines.
Proto-oncogene proteins c-mdm2 are a family of proteins that play a role in regulating the activity of the tumor suppressor protein p53. p53 is a transcription factor that is activated in response to cellular stress, such as DNA damage or oncogene activation, and helps to prevent the development of cancer by promoting cell cycle arrest, apoptosis (programmed cell death), and DNA repair. Proto-oncogene proteins c-mdm2 can bind to and inhibit the activity of p53, thereby preventing it from carrying out its tumor suppressor functions. This can contribute to the development of cancer by allowing cells with damaged DNA to continue to divide and proliferate. Proto-oncogene proteins c-mdm2 are therefore considered to be oncogenes, which are genes that have the potential to cause cancer.
Green Fluorescent Proteins (GFPs) are a class of proteins that emit green light when excited by blue or ultraviolet light. They were first discovered in the jellyfish Aequorea victoria and have since been widely used as a tool in the field of molecular biology and bioimaging. In the medical field, GFPs are often used as a marker to track the movement and behavior of cells and proteins within living organisms. For example, scientists can insert a gene for GFP into a cell or organism, allowing them to visualize the cell or protein in real-time using a fluorescent microscope. This can be particularly useful in studying the development and function of cells, as well as in the diagnosis and treatment of diseases. GFPs have also been used to develop biosensors, which can detect the presence of specific molecules or changes in cellular environment. For example, researchers have developed GFP-based sensors that can detect the presence of certain drugs or toxins, or changes in pH or calcium levels within cells. Overall, GFPs have become a valuable tool in the medical field, allowing researchers to study cellular processes and diseases in new and innovative ways.
Receptors, cell surface are proteins that are located on the surface of cells and are responsible for receiving signals from the environment. These signals can be chemical, electrical, or mechanical in nature and can trigger a variety of cellular responses. There are many different types of cell surface receptors, including ion channels, G-protein coupled receptors, and enzyme-linked receptors. These receptors play a critical role in many physiological processes, including sensation, communication, and regulation of cellular activity. In the medical field, understanding the function and regulation of cell surface receptors is important for developing new treatments for a wide range of diseases and conditions.
Arrestin beta 2
Arrestin beta 1
Thyrotropin-releasing hormone receptor
G protein-coupled receptor kinase 2
G protein-coupled receptor kinase 3
G protein-coupled receptor kinase
Raymond C. Stevens
Retinal degeneration (rhodopsin mutation)
Alpha-2C adrenergic receptor
Martin J. Lohse
G protein-coupled receptor
Arun Kumar Shukla
Mouse cones require an arrestin for normal inactivation of phototransduction
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- Arrestins are proteins that arrest the activity of G protein-coupled receptors (GPCRs). (nih.gov)
- The two β -arrestins, β -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiologic functions. (aspetjournals.org)
- Recent structural, biophysical, and biochemical studies have provided novel insights into how β -arrestins bind to activated GPCRs and downstream effector proteins. (aspetjournals.org)
- Significance Statement The two β-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. (aspetjournals.org)
- In another recent survey by Lin (2008), arrestin-related transport adaptors were also found to target specific plasma-membrane proteins for endocytic downregulation by recruiting the ubiquitin E3 ligase Rsp5. (bioskinrevive.com)
- This resulted in the identification of the yeast proteins category of arrestin-related trafficking adaptors (ARTs)which includes nine members which have conserved arrestin and PY motifs, seven which are predicted to really have the arrestin foldand hence Cvs7 was renamed Artwork1. (bioskinrevive.com)
- It is concluded that PTH stimulates ERK1/2 through several distinct signal transduction pathways: an early G protein-dependent pathway meditated by PKA and PKC and a late pathway independent of G proteins mediated through beta-arrestins. (duke.edu)
- Arrestins (abbreviated Arr) are a family of proteins which are important in the regulation of signal transduction G-protein coupled receptors, which at first was discovered, as part of a conserved two step mechanism for regulating the activity of G protein-coupled receptors (GPCR) in rhodopsin visual system by Ursula Kuhn found Scott court, and β-called Global Martin J. Lohse system and kidney and colleagues. (arrestins.com)
- Scholars@Duke publication: Distinct beta-arrestin- and G protein-dependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. (duke.edu)
- This later phase of ERK1/2 activation at 30-60 min was blocked by depletion of cellular beta-arrestin 2 and beta-arrestin 1 by small interfering RNA. (duke.edu)
- Furthermore, stimulation of hPTH1R with PTH analogues, [Trp1]PTHrp-(1-36) and [d-Trp12,Tyr34]PTH-(7-34), selectively activated G(s)/PKA-mediated ERK1/2 activation or G protein-independent/beta-arrestin-dependent ERK1/2 activation, respectively. (duke.edu)
- The binding of beta-arrestin, a cytoplasmic protein, to an activated receptor deactivates the GPCR signaling and initiates the translocation of the receptor into the cell where the ligand is removed, and the receptor is recycled back to the cell membrane. (aatbio.com)
- By attaching a fluorescent label, such as GFP, to beta-arrestin, the location of the receptor arrestin complex can be monitored. (aatbio.com)
- Since desensitization only occurs with an activated receptor, monitoring beta-arrestin translocation and subsequent receptor recycling provides a reliable method to detect the activation of a GPCR target. (aatbio.com)
- Cell Meter™ Beta-Arrestin translocation GPCR Signaling Kit provides a powerful functional assay to screen activities of target compounds against known or orphan GPCR targets via fluorescence imaging. (aatbio.com)
- Add 10 µL of ddH 2 O to the vial of beta-arrestin-GFP DNA (Component A), mix well to have the final concentration of 1 µg/µL. (aatbio.com)
- Mix 3 µg of DNA [for example, 1.5 µg of Beta-arrestin-GFP DNA stock solution and 1.5 µg DNA of the GPCR that you are interested] with 200 µL of serum-free medium. (aatbio.com)
- Monitor the beta-arrestin translocation induced by the receptor activation under a fluorescence microscope with the FITC filter (Ex/Em = 488/530 nm). (aatbio.com)
- The movie shows the movement of GFP-beta-arrestin after TRH addition. (rochester.edu)
- the phospho-receptor binds to beta-arrestin. (rochester.edu)
- It really is interesting in this respect that a accurate' mammalian arrestin, -arrestin 2, has been proven to do something as an adaptor for the WW-domain-containing Electronic3 ubiquitin ligase NEDD4 to market agonist-stimulated ubiquitination of the 2-adrenergic receptor (Shenoy em et al /em , 2008). (bioskinrevive.com)
- arrestins possess an amphipathic helix (helix 1) that's sequestered in to the inactive conformation of the N-terminal domain and is normally presumably released on activation by receptor engagement, whereas -arrestins usually do not. (bioskinrevive.com)
- GPCR kinases (GRKs) and β-arrestins are activated by agonist-bound GPCRs and interact with the receptor cavity. (drgpcr.com)
- Notably, GRKs phosphorylate active GPCRs, enabling high-affinity arrestin binding, which is crucial for receptor internalization. (drgpcr.com)
- With different collaborators we solved crystal structures of all four vertebrate arrestins, the arrestin-rhodopsin complex, and pre-activated arrestin-3 in the absence of receptor. (hstalks.com)
- We identified key residues responsible for receptor preference of arrestins. (hstalks.com)
- The formation of functional complexes involving GPCRs and β-arrestins hinges on their specific conformational states, influenced by their intricate three-dimensional structures. (drgpcr.com)
- read more constructed enhanced arrestins that bind active unphosphorylated GPCRs. (hstalks.com)
- We proved that monomeric GPCRs are necessary and sufficient for GRK phosphorylation and arrestin binding. (hstalks.com)
- While it is well established that normal inactivation of photoexcited rhodopsin, the GPCR of rod phototransduction, requires arrestin (Arr1), it has been controversial whether the same requirement holds for cone opsin inactivation. (nih.gov)
- We showed that enhanced mutants of visual arrestin-1 compensate for defects in rhodopsin phosphorylation in vivo. (hstalks.com)
- Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. (bvsalud.org)
- The hypothesis arises that GPCR and β-arrestin-centered effector complexes vary based on subcellular localization, potentially scaffolding distinct signaling platforms. (drgpcr.com)
- However, it is now well recognized that both β -arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. (aspetjournals.org)
- The useful homology of Cvs7 to mammalian arrestins was set up by verifying that the mutation of conserved residues within the arrestin motif ablated Cvs7 function. (bioskinrevive.com)
- This review also highlights potential therapeutic implications of these studies and discusses strategies that could prove useful for targeting specific β -arrestin-regulated signaling pathways for therapeutic purposes. (aspetjournals.org)
- β-Arrestins facilitate this process by interacting with adapter protein 2 (AP-2) and clathrin. (drgpcr.com)
- The thioredoxin-interacting protein (TXNIP) is a multi-functional protein of the alpha-arrestin family implicated in redox regulation, glucose uptake, cell proliferation, and activation of NLRP3. (cdc.gov)
- arrestin 2 will not include any legitimate PY motifs, but was nevertheless proven to bind to NEDD4. (bioskinrevive.com)
- By means of recordings from cones of mice with one or both arrestins knocked out, this investigation establishes that a visual arrestin is required for normal cone inactivation. (nih.gov)
- Studies with β -arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by β -arrestin-1 and/or -2. (aspetjournals.org)
- The outcome of studies with β-arrestin mutant mice and cultured cells, complemented by novel insights into β-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific β-arrestin functions. (aspetjournals.org)
- We identified arrestin elements involved in scaffolding ASK1-MKK4/4-JNK1/2/3 cascades and constructed novel tools for manipulation of JNK signaling, including short peptides that facilitate JNK3 activation in cells. (hstalks.com)
- Dual arrestin expression in cones could be a holdover from ancient genome duplication events that led to multiple isoforms of arrestin, allowing evolutionary specialization of one form while the other maintains the basic function. (nih.gov)
- Research focus: structure and function of arrestins. (hstalks.com)
- Furthermore to ARTs, Vps26a component of the five-subunit retromer complex involved in retrograde transport from endosomes to the em trans /em -Golgi networkhas been STMY shown to present the same overall fold as the arrestins (Shi em et al /em , 2006). (bioskinrevive.com)
- Hence, the mammalian arrestins have got expanded from 4 preliminary memberstwo visible and two -arrestinsto 14 members with the addition of 6 -arrestins (ARTs) and 4 VPS26 members (which buy Clofarabine talk about higher sequence similarity with -arrestins). (bioskinrevive.com)
- Following a short summary of recent structural studies, this review primarily focuses on β -arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of β -arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. (aspetjournals.org)
- GPCR function is modulated by a pair of proteins known as beta-arrestin-1 and -2 ( barr1 and barr2, respectively), which can terminate GPCR signaling and/or mediate GPCR-independent signaling. (nih.gov)
- The high expression of recoverin and arrestin-1 in kidney tumors suggests the use of these proteins in future as a marker for the diagnosis or even as a potential target for immunotherapy. (eco-vector.com)
- Arrestins (abbreviated Arr) are a family of proteins which are important in the regulation of signal transduction G-protein coupled receptors, which at first was discovered, as part of a conserved two step mechanism for regulating the activity of G protein-coupled receptors (GPCR) in rhodopsin visual system by Ursula Kuhn found Scott court, and β-called Global Martin J. Lohse system and kidney and colleagues. (arrestins.com)
- Receptor phosphorylation may attenuate signaling per se and/or may facilitate recruitment of arrestin proteins ( Krupnick and Benovic, 1998 ). (jneurosci.org)
- Structural studies including determination of 3D structures of ligands, receptors, receptors with associated G-proteins, beta-arrestin etc. (nih.gov)
- 1. Differential nucleocytoplasmic shuttling of beta-arrestins. (nih.gov)
- 2. Subcellular localization of beta-arrestins is determined by their intact N domain and the nuclear export signal at the C terminus. (nih.gov)
- 7. Termination of protease-activated receptor-1 signaling by beta-arrestins is independent of receptor phosphorylation. (nih.gov)
- 19. beta -Arrestins regulate protease-activated receptor-1 desensitization but not internalization or Down-regulation. (nih.gov)
- Activated ß-arrestin-1 (yellow) binds a G-protein coupled receptor (green) that crosses the cell membrane (gray). (nih.gov)
- It has been reported recently that T cells lacking β-arrestin-2, a G protein-coupled receptor regulatory protein, demonstrate impaired migration in vitro. (jci.org)
- 6. The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. (nih.gov)
- GRK1-dependent phosphorylation of S and M opsins and their binding to cone arrestin during cone phototransduction in the mouse retina. (nih.gov)
- Here we show that allergen-sensitized mice having a targeted deletion of the β-arrestin-2 gene do not accumulate T lymphocytes in their airways, nor do they demonstrate other physiological and inflammatory features characteristic of asthma. (jci.org)
- Using permanent and primary human bronchial epithelial (HBE) cells at air-liquid interface, we show that DEPs activate the human MMP-1 gene via RAS and subsequent activation of RAF-MEK-ERK1/2 mitogen-activated protein kinase signaling, which can be scaffolded by β-arrestins. (nih.gov)
- The gene, arrestin domain containing 5 ( ARRDC5 ) is present in several mammalian species and controls the last step in sperm maturation. (nih.gov)
- A previous study found that overactivity and inactivation of another gene in the arrestin domain containing family, ARRDC4 , found in the male reproductive tract, resulted in sperm with less ability to move and less ability to fertilize an egg. (nih.gov)
- In contrast, the airway inflammatory response to LPS, an event not coordinated by Th2 cells, is fully functional in mice lacking β-arrestin-2. (jci.org)
- Aim: To evaluate the possibility of using arrestin-1 (Arr-1), recoverin (Rec) and autoantibodies against arrestin-1 (AAA1) and recoverin (AAR) as a kidney tumor biomarker. (eco-vector.com)
- Compared to previously determined inactive state structures, activated β-arrestin-1 has pronounced structural changes. (nih.gov)
- These scientists found similar changes between the active and inactive states of arrestin p44. (nih.gov)
- 13. Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. (nih.gov)
- The researchers were studying the interactions between β-arrestin-1 and a human GPCR called the V2 vasopressin receptor. (nih.gov)
- 8. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. (nih.gov)
- Here we report the use of extracellular vesicles, known as arrestin domain containing protein 1 [ARRDC1]-mediated microvesicles (ARMMs), for packaging and intracellular delivery of a myriad of macromolecules, including the tumor suppressor p53 protein, RNAs, and the genome-editing CRISPR-Cas9/guide RNA complex. (nih.gov)
- This ELISA test kit for detection of Human beta-arrestin,ARRB should be stored refrigerated at temperatures between 2 and 8 degrees Celsius. (arrestins.com)
- This report provides the first evidence that β-arrestin-2 is required for the manifestation of allergic asthma. (jci.org)