Inward-rectifier potassium channels (Kir, IRK) are a specific subset of potassium channels. To date, seven subfamilies have been identified in various mammalian cell types, plants, and bacteria. They are the targets of multiple toxins, and malfunction of the channels has been implicated in several diseases. IRK channels possess a pore domain, homologous to that of voltage-gated ion channels, and flanking transmembrane segments (TMSs). They may exist in the membrane as homo- or heterooligomers and each monomer possesses between 2 and 4 TMSs. In terms of function, these proteins transport potassium (K+), with a greater tendency for K+ uptake than K+ export. A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell. ...
TY - JOUR. T1 - Compound-induced block of ion channel pore function. T2 - Inward-rectifier potassium channels as a model. AU - Furutani, Kazuharu. AU - Hibino, Hiroshi. AU - Inanobe, Atsushi. AU - Kurachi, Yoshihisa. PY - 2009/12/1. Y1 - 2009/12/1. N2 - Small chemical compounds modulate ion channel functions. This is the reflection of ligand interactions with ion channels at their various sites. Many biophysical and biochemical researches have been performed on this subject and have provided important basic concepts on the structure-functional relationships of ion channels. Especially, ion channel blockers have been excellent tools for biophysical studies of ion channels and some of them are actually used for treating various diseases. The mechanisms underlying the blocking action of various chemical compounds, however, remain largely unknown at the atomic level, partly because of the promiscuous nature of the reaction. As one of the attempts to overcome the problem, we have adopted a novel ...
This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium. Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (By similarity).
This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium (By similarity).
Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ16 may be involved in the regulation of fluid and pH balance. In the kidney, together with KCNJ10, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules (PubMed:24561201 ...
Since the mechanism of salt impairing NO-induced vascular relaxation is not fully clear, this study was designed to investigate the role of potassium (K+) channels in the vasodilatory effects of NO donor in salt loaded rats. Isolated thoracic aortic rings of adult male albino rats fed 8% NaCl containing diet for six weeks were used for isometric tension recording using PowerLab tissue bath system. The recorded data revealed that high salt diet (HS) did not change the relaxation responses to sodium nitroprusside (SNP, an NO donor) in rats thoracic aortic rings. SNP-induced relaxation in salt loaded rats was significantly lower in rings contracted by high K+ than phenylephrine (PE, a selective α1-adrenergic receptor agonist). On the other hand, incubation of aortic rings from salt loaded rats with inward-rectifier K+ (KIR) channel blockers either individually or simultaneously with other K+ channel blockers significantly inhibited SNP-induced relaxation in PE-contracted rings; however incubation ...
A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell. By convention, inward current (positive charge moving into the cell) is displayed in voltage clamp as a downward deflection, while an outward current (positive charge moving out of the cell) is shown as an upward deflection. At membrane potentials negative to potassiums reversal potential, inwardly rectifying K+ channels support the flow of positively charged K+ ions into the cell, pushing the membrane potential back to the resting potential. This can be seen in figure 1: when the membrane potential is clamped negative to the channels resting potential (e.g. -60 mV), inward current flows (i.e. positive charge flows into the cell). However, when the ...
A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell. By convention, inward current (positive charge moving into the cell) is displayed in voltage clamp as a downward deflection, while an outward current (positive charge moving out of the cell) is shown as an upward deflection. At membrane potentials negative to potassiums reversal potential, inwardly rectifying K+ channels support the flow of positively charged K+ ions into the cell, pushing the membrane potential back to the resting potential. This can be seen in figure 1: when the membrane potential is clamped negative to the channels resting potential (e.g. -60 mV), inward current flows (i.e. positive charge flows into the cell). However, when the ...
We demonstrate that tamoxifen, a synthetic nonsteroidal triphenylethylene derivative, which has estrogenic, antiestrogenic effects, 4-hydroxytamoxifen, an active metabolite of tamoxifen, and raloxifene, the selective estrogen receptor modulator used to treat osteoporosis in postmenopausal women, inhibit the strong inward rectifier potassium channels Kir2.x. The order of inhibition for all three drugs was Kir2.3 , Kir2.1 ∼ Kir2.2. The inhibition of Kir2.x current by tamoxifen, 4-hydroxytamoxifen, and raloxifene occurred slowly (T1/2 ∼ 6 min), and the currents only partially recovered after washout (∼30%). Tamoxifen also inhibited IK1 in cat atrial and ventricular myocytes, and the effects were greater in the former than the latter.. The inhibition induced by tamoxifen, 4-hydroxytamoxifen, and raloxifene was concentration-dependent but voltage-independent. The potency of tamoxifen to inhibit Kir2.1 channel was greater than 4-hydroxytamoxifen and raloxifene. The IC50 of inhibition by ...
Heteromultimerization between different potassium channel subunits can generate channels with novel functional properties and thus contributes to the rich functional diversity of this gene family. The inwardly rectifying potassium channel subunit Kir5.1 exhibits highly selective heteromultimerization with Kir4.1 to generate heteromeric Kir4.1/Kir5.1 channels with unique rectification and kinetic properties. These novel channels are also inhibited by intracellular pH within the physiological range and are thought to play a key role in linking K+ and H+ homeostasis by the kidney. However, the mechanisms that control heteromeric K+ channel assembly and the structural elements that generate their unique functional properties are poorly understood. In this study we identify residues at an intersubunit interface between the cytoplasmic domains of Kir5.1 and Kir4.1 that influence the novel rectification and gating properties of heteromeric Kir4.1/Kir5.1 channels and that also contribute to their pH sensitivity
Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein has a greater tendency to allow potassium to flow into a cell rather than out of a cell. Eight transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Feb 2013 ...
ATP-sensitive potassium channels (KATP) regulate a range of biological activities by coupling membrane excitability to the cellular metabolic state. In particular, it has been proposed that KATP channels and specifically, the channel subunits Kir6.1 and SUR2B, play an important role in the regulation of vascular tone. However, recent experiments have suggested that KATP channels outside the vascular smooth muscle compartment are the key determinant of the observed behavior. Thus, we address the importance of the vascular smooth muscle KATP channel, using a novel murine model in which it is possible to conditionally delete the Kir6.1 subunit. Using a combination of molecular, electrophysiological, in vitro, and in vivo techniques, we confirmed the absence of Kir6.1 and KATP currents and responses specifically in smooth muscle. Mice with conditional deletion of Kir6.1 showed no obvious arrhythmic phenotype even after provocation with ergonovine. However, these mice were hypertensive and vascular ...
ATP-sensitive K(+) (K(ATP)) channels, comprised of pore-forming Kir6.x and regulatory SURx subunits, play important roles in many cellular functions; because of their sensitivity to inhibition by intracellular ATP, K(ATP) channels provide a link between cell metabolism and membrane electrical activity. We constructed structural homology models of Kir6.2 and a series of Kir6.2 channels carrying mutations within the putative ATP-binding site. Computational docking was carried out to determine the conformation of ATP in its binding site. The Linear Interaction Energy (LIE) method was used to estimate the free-energy of ATP binding to wild-type and mutant Kir6.2 channels. Comparisons of the theoretical binding free energies for ATP with those determined from mutational experiments enabled the identification of the most probable conformation of ATP bound to the Kir6.2 channel. A set of LIE parameters was defined that may enable prediction of the effects of additional Kir6.2 mutations within the ATP binding
InterPro provides functional analysis of proteins by classifying them into families and predicting domains and important sites. We combine protein signatures from a number of member databases into a single searchable resource, capitalising on their individual strengths to produce a powerful integrated database and diagnostic tool.
1. ATP-sensitive potassium (KATP) channels are composed of pore-forming Kir6.2 and regulatory SUR subunits. A truncated isoform of Kir6.2, Kir6.2DeltaC26, forms ATP-sensitive channels in the absence of SUR1, suggesting the ATP-inhibitory site lies on Kir6.2. 2. Previous studies have shown that mutation of the lysine residue at position 185 (K185) in the C-terminus of Kir6.2 to glutamine, decreased the channel sensitivity to ATP without affecting the single-channel conductance or the intrinsic channel kinetics. This mutation also impaired 8-azido[32P]-ATP binding to Kir6.2. 3. To determine if K185 interacts directly with ATP, we made a range of mutations at this position, and examined the effect on the channel ATP sensitivity by recording macroscopic currents in membrane patches excised from Xenopus oocytes expressing wild-type or mutant Kir6.2DeltaC26. 4. Substitution of K185 by a positively charged amino acid (arginine) had no substantial effect on the sensitivity of the channel to ATP. Mutation to a
MS Model, Version 5.0 ********************** //*************************** MScell.p ********************** // Tom Sheehan [email protected] [email protected] 703-538-836 //***************************************************************************** *relative *cartesian *asymmetric *lambda_warn *set_global ELEAK -0.070 //*set_global RA 1.0 //*set_global RM 8.695652 1.8 1.83-0.0295 1.86-0.029 1.96-0.0275 2.16-0.025 *set_global RM 1.8 //1.8-0.03 //*set_global CM 0.010 //change Cm to account for no spines - make 3x higher? 0.03 0.025 *set_global CM 0.03 *set_global EREST_ACT -0.085 *start_cell /library/tert_dend tert_dend none 35.927 0 0 0.80 tert_dend2 . 35.927 0 0 0.80 tert_dend3 . 35.927 0 0 0.80 tert_dend4 . 35.927 0 0 0.80 tert_dend5 . 35.927 0 0 0.80 tert_dend6 . 35.927 0 0 0.80 tert_dend7 . 35.927 0 0 0.80 tert_dend8 . 35.927 0 0 0.80 tert_dend9 . 35.927 0 0 0.80 tert_dend10 . 35.927 0 0 0.80 tert_dend11 . 35.927 0 0 0.80 *makeproto /library/tert_dend *start_cell /library/sec_dend sec_dend none ...
from neuron import h import matplotlib.pyplot as plt import numpy as np import seaborn as sns soma = h.Section() dend = h.Section() soma.L = 10 soma.diam = 10 soma.Ra = 1000 soma.insert(pas) soma.g_pas = 1e-5 soma.cm = 1 dend.L = 200 dend.nseg = 47 dend.diam = 3 dend.Ra = 1000 dend.insert(pas) dend.g_pas = 1e-3 dend.cm = 1 dend.connect(soma(0), 0) # dend.connect(soma(0), 1) istim = h.IClamp(1.0, dend) istim.amp = 0.2 istim.delay = 100 istim.dur = 30 vdlist = [] vdlist.append(h.Vector()) vdlist.append(h.Vector()) vdlist.append(h.Vector()) vs = h.Vector() t = h.Vector() vdlist[0].record(dend(1.0)._ref_v) vdlist[1].record(dend(0.5)._ref_v) vdlist[2].record(dend(0.0)._ref_v) vs.record(soma(0.5)._ref_v) t.record(h._ref_t) h.load_file("stdrun.hoc") h.init() h.tstop = 200 h.run() # Plotting code from here rows = 2 fig = plt.figure(); plot_num = 1; ax2 = fig.add_subplot(rows, 1, plot_num); plot_num += 1; ax2.set_ylabel(Vd) ax2.set_xlabel(t) ax2.xaxis.set_ticks(np.arange(0, h.tstop, 10)) ...
Anionic phospholipids (e.g. PIP2) activate all inward rectifier K+ (Kir) channels and degradation of phospholipids by endogenous lipid phosphatases or phospholipases is a well-accepted mechanism for Kir current rundown in excised membrane patches. The rate of Kir current rundown varies and is inversely correlated to the PIP-binding affinity of the channel being studied, with rundown being faster for channels that bind PIPs less strongly [14-16].. Sensitivity of KATP channels to phosphoinositide turnover was first demonstrated in giant membrane patches from cardiac myocytes, where native Kir6.2/SUR2A channels are abundant [17]. These channels run down rapidly in excised patches exposed to nucleotide-free solutions, but following exposure to intracellular MgATP their activity is (at least partially) restored, as seen by comparing the current in control solution before and after ATP application. This increase in channel activity was mimicked by intracellular application of PIP2, and reversed by ...
KATP channels are unique amongst known potassium channels in requiring an unrelated ABC protein subunit (SUR1) in addition to an inward rectifier K channel (Kir6.2) subunit (Inagaki et al., 1995a). In other cloned inward rectifiers, strong inward rectification is controlled by a pore-lining residue in the M2 transmembrane segment (Fakler et al., 1994; Ficker et al., 1994; Lopatin et al., 1994; Lu and MacKinnon, 1994; Stanfield et al., 1994). Mutation of the corresponding residue in Kir6.2 from asparagine to aspartate results in generation of KATP channels that rectify strongly in the presence of cytoplasmic spermine (Fig. 1 b; Clement et al., 1997; Shyng et al., 1997), single channel conductance being unaltered and channels remaining sensitive to inhibition by ATP (Shyng et al., 1997). The requirement for SUR1 to form active channels still raises the possibility that the receptor might also contribute to the pore, and perhaps reduce or otherwise alter the number of Kir6.2 subunits involved. The ...
from simpleNrnLib import * def simpleComputational(): dend = make_section("dend") dend.L = 1000 dend.diam = 10 dend.nseg = 21 dend.insert(pas) soma = make_section("soma") soma.L = 1000 soma.diam = 10 soma.nseg = 21 soma.insert(pas) soma.connect(dend,1,0) # connect dend(1) to soma(0) for sec in h.allsec(): sec.Ra = 200 sec.cm = 5.001 for seg in sec: seg.pas.g = 5e-5 seg.pas.e = 0 iClamp = make_iClamp(dend(0)) iClamp.delay = 10 iClamp.amp = 1.2 iClamp.dur = 500000 voltage = h.RangeVarPlot("v") voltage.begin(0) voltage.end(1) tstop = 5000 v_init = -60 h.dt = 0.025 h.finitialize(v_init) h.fcurrent() run(tstop) vVec = h.Vector() pVec = h.Vector() voltage.to_vector(vVec,pVec) return pVec, ...
Morphology file for Golgi cell // A single compartment neuron with a spherical soma yielding // an Rin (78 MegaOhm) and a time-constant (24 msec) as tabulated in Midtgaard (1992). // The resulting Cm is 0.31 nF, assuming a specific membrane capacitance of 0.01 (F/m^2). // The resulting surface area is 0.31e5 um^2. // Written by RM (27/11/95). // changed /library/soma to /library/interneuron/soma on 16/4/96 MAEX *relative *set_compt_param ELEAK {ELEAK} *set_compt_param EREST_ACT {EREST_ACT} *set_compt_param RM 3.03 // 2.4000 // 24 000 ohm.cm^2 *set_compt_param RA 1.0000 // *set_compt_param CM 0.0100 // 1microF/cm^2 // The entire neuron has now about the same membrane surface area // as the original single soma compartment. In addition, all // compartments have the same area. *compt /library/granule/soma soma none 0.000 0.000 0.000 12.25 // 30.0 // 99.33 *compt /library/granule/dend dend[0] soma 0.0 15.0 0.0 5.0 dend[1] dend[0] 0.0 15.0 0.0 5.0 dend[2] dend[1] 0.0 18.75 0.0 4.0 dend[3] dend[2] 0.0 ...
Inwardly rectifying potassium (Kir) channels form gates in the cell membrane that regulate the flow of K(+) ions into and out of the cell, thereby influencing the membrane potential and electrical signaling of many cell types, including neurons and cardiomyocytes. Kir-channel function depends on other cellular proteins that aid in the folding of channel subunits, assembly into tetrameric complexes, trafficking of quality-controlled channels to the plasma membrane, and regulation of channel activity at the cell surface. We used the yeast Saccharomyces cerevisiae as a model system to identify proteins necessary for the functional expression of a mammalian Kir channel at the cell surface. A screen of 376 yeast strains, each lacking one nonessential protein localized to the early secretory pathway, identified seven deletion strains in which functional expression of the Kir channel at the plasma membrane was impaired. Six deletions were of genes with known functions in trafficking and lipid ...
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In HAECs, the molecular diversity of Kir2 subunits at the transcript level is higher than the diversity of functional Kir. While for Kir2.3 this discrepancy could be explained by undetectable levels of protein expression due to very low transcription, the transcript level of Kir2.4 is similar to that of Kir2.1, suggesting that Kir2.4 functional expression is regulated at a posttranscriptional level. A discrepancy between the heterogeneity of K+ channels at the transcript and functional levels was reported previously for Kir2.x channels in human myoblasts (8) and for voltage-gated K+ channels in rat cardiomyocytes (2, 49), and it has been proposed that translational-posttranslational steps may contribute a rate-limiting step to channel expression (38). Protein expression of Kir2.x subunits in HAECs is consistent with the functional expression of the channels.. The peak IK unitary conductance levels in HAECs (25 and 35 pS) are similar to previously reported values in human umbilical vein ...
HEK293-HuCACNA1C/NEUROD1/CACNA2D1/KCNJ2 cell line is a hypotriploid human cell line, which has been transfected with a human calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C), a human neuronal differentiation 1 (NEUROD1), a human calcium channel, voltage-dependent, alpha 2/delta subunit 1 (CACNA2D1) and a human potassium inwardly-rectifying channel, subfamily J, member 2 (KCNJ2) to allow stably express of the human CACNA1C, NEUROD1, CACNA2D1 and KCNJ2. It is an example of a cell line tr
The present study concludes on the basis of independent kinetic and pharmacological evidence that two components of IK are present in canine atrial and ventricular myocytes. Two tail current components can be distinguished kinetically on the basis of (1) two exponential components describing IK deactivation, (2) differences in the voltage and time dependence of activation of each tail component, and (3) the differential sensitivity of each component to reduced [K+]o. IK components described kinetically (IKe1 and IKe2) were subsequently compared with components identified pharmacologically by using E-4031. The voltage dependence, activation kinetics, and rectification properties of E-4031-sensitive current (typically defined as IKr) were analogous to IKe2 (defined kinetically), whereas E-4031-insensitive current (IKs) was analogous to the more rapid IKe1 in atrial and ventricular myocytes. These similarities argue against the possibility that pharmacologically defined deactivation of IKr is ...
Effects of PPIs on ATP sensitivity at the single-channel level. Single-channel KATP current recorded in an inside-out patch at 0 mV from a rat ventricular cell
Դիգոքսինի ազդեցության հիմնական մեխանիզմը ներառում է սրտամկանում նատրիում/կալիումական ադենոզին եռֆոսֆատազի ( Na + / K + ATPազ) արգելակումը: Այս արգելակումը հանգեցնում է ներբջջային նատրիումի մակարդակի բարձրացմանը, ինչը հետևանք է նատրիումի-կալցիումի փոխարկիչի ակտիվության նվազեցման, որը սովորաբար բջջի մեջ ներմուծում է նատրիումի երեք իոն եւ բջջից դուրս տեղափոխում կալցիումի մեկ իոն: Այս փոխարկիչի անգործությունը առաջացնում է ներբջջային կալցիումի կոնցենտրացիայի ավելացում, որը հասանելի է կծկում առաջացնող սպիտակուցներին: Կալցիումի բարձր մակարդակը ...
Andersen-Tawil Syndrome is a genetic condition that causes periods of muscle weakness (periodic paralysis), changes in heart rhythm (arrhythmia), and intellectual and developmental abnormalities. Other features can include low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Speak to a genetic counselor or a medical geneticist if you have questions about Andersen-Tawil syndrome. ...
TY - JOUR. T1 - Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism. AU - Lin, Yu Wen. AU - Bushman, Jeremy D.. AU - Yan, Fei Fei. AU - Haidar, Sara. AU - MacMullen, Courtney. AU - Ganguly, Arupa. AU - Stanley, Charles A.. AU - Shyng, Show-Ling. PY - 2008/4/4. Y1 - 2008/4/4. N2 - The inwardly rectifying potassium channel Kir6.2 is the pore-forming subunit of the ATP-sensitive potassium (KATP) channel, which controls insulin secretion by coupling glucose metabolism to membrane potential in β-cells. Loss of channel function because of mutations in Kir6.2 or its associated regulatory subunit, sulfonylurea receptor 1, causes congenital hyperinsulinism (CHI), a neonatal disease characterized by persistent insulin secretion despite severe hypoglycemia. Here, we report a novel KATP channel gating defect caused by CHI-associated Kir6.2 mutations at arginine 301 (to cysteine, glycine, histidine, or proline). These mutations in ...
Derst, C.; Wischmeyer, E.; Preisig-Mueller, R.; Spauschus, A.; Konrad, M.; Hensen, P.; Jeck, N.; Seyberth, H. W.; Daut, J.; Karschin, A.: A hyperprostaglandin E syndrome mutation in Kir1.1 (renal outer medullary potassium) channels reveals a crucial residue for channel function in Kir1.3 channels. Journal of Biological Chemistry 273, pp. 23884 - 23891 (1998 ...
Polyamine block of inwardly rectifying potassium (Kir) channels underlies their key functional property of preferential conduction of inward K+ currents (Ficker et al., 1994; Lopatin et al., 1994, 1995; Fakler et al., 1995). As a rapid and voltage-dependent process, polyamine-mediated inward rectification provides a mechanism for moment-to-moment regulation of K+ currents in excitable tissues, shaping both the action potential and resting membrane potential in tissues such as myocardium (Bianchi et al., 1996; Lopatin et al., 2000; Priori et al., 2005; Schulze-Bahr, 2005). Akin to the ongoing challenges to understanding voltage-dependent gating of the Kv channel family, development of a molecular description of steeply voltage-dependent polyamine block is an important issue for understanding the fundamental basis of strongly rectifying Kir channel activity.. Appropriate kinetic models describe polyamine block as a multistep process, incorporating sequentially linked "shallow" and "deep" binding ...
TY - JOUR. T1 - ATP sensitive potassium channel openers. T2 - A new class of ocular hypotensive agents. AU - Roy Chowdhury, Uttio. AU - Dosa, Peter I.. AU - Fautsch, Michael P. PY - 2016/3/2. Y1 - 2016/3/2. N2 - ATP sensitive potassium (KATP) channels connect the metabolic and energetic state of cells due to their sensitivity to ATP and ADP concentrations. KATP channels have been identified in multiple tissues and organs of the body including heart, pancreas, vascular smooth muscles and skeletal muscles. These channels are obligatory hetero-octamers and contain four sulfonylurea (SUR) and four potassium inward rectifier (Kir) subunits. Based on the particular type of SUR and Kir present, there are several tissue specific subtypes of KATP channels, each with their own unique set of functions. Recently, KATP channels have been reported in human and mouse ocular tissues. In ex vivo and in vivo model systems, KATP channel openers showed significant ocular hypotensive properties with no appearance of ...
Introduction: Andersen-Tawil syndrome (ATS) due to Kir2.1mutations typically manifests as periodic paralysis, cardiac arrhythmias and developmental abnormalities but is often difficult to diagnose clinically. This study was undertaken to determine whether sarcolemmal dysfunction could be identified with muscle velocity recovery cycles (MVRCs). Methods: Eleven genetically confirmed ATS patients and 20 normal controls were studied. MVRCs were recorded with 1, 2, and 5 conditioning stimuli and with single conditioning stimuli during intermittent repetitive stimulation at 20 Hz, in addition to the long exercise test. Results: ATS patients had longer relative refractory periods (P , 0.0001) and less early supernormality, consistent with membrane depolarization. Patients had reduced enhancement of late supernormality with 5 conditioning stimuli (P , 0.0001), and less latency reduction during repetitive stimulation (P , 0.001). Patients were separated completely from controls by combining MVRC and ...
AIMS/HYPOTHESIS: The pancreatic ATP-sensitive potassium (KATP) channel plays a pivotal role in linking beta cell metabolism to insulin secretion. Mutations in KATP channel genes can result in hypo- or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, respectively. To date, all patients affected by neonatal diabetes due to a mutation in the pore-forming subunit of the channel (Kir6.2, KCNJ11) are heterozygous for the mutation. Here, we report the first clinical case of neonatal diabetes caused by a homozygous KCNJ11 mutation. METHODS: A male patient was diagnosed with diabetes shortly after birth. At 5 months of age, genetic testing revealed he carried a homozygous KCNJ11 mutation, G324R, (Kir6.2-G324R) and he was successfully transferred to sulfonylurea therapy (0.2 mg kg(-1) day(-1)). Neither heterozygous parent was affected. Functional properties of wild-type, heterozygous and homozygous mutant KATP channels were examined after heterologous expression in
d_iris ,- dist(iris2) # method=man # is a bit better hc_iris ,- hclust(d_iris, method = complete) iris_species ,- rev(levels(iris[,5])) library(dendextend) dend ,- as.dendrogram(hc_iris) # order it the closest we can to the order of the observations: dend ,- rotate(dend, 1:150) # Color the branches based on the clusters: dend ,- color_branches(dend, k=3) #, groupLabels=iris_species) # Manually match the labels, as much as possible, to the real classification of the flowers: labels_colors(dend) ,- rainbow_hcl(3)[sort_levels_values( as.numeric(iris[,5])[order.dendrogram(dend)] )] # We shall add the flower type to the labels: labels(dend) ,- paste(as.character(iris[,5])[order.dendrogram(dend)], (,labels(dend),), sep = ) # We hang the dendrogram a bit: dend ,- hang.dendrogram(dend,hang_height=0.1) # reduce the size of the labels: # dend ,- assign_values_to_leaves_nodePar(dend, 0.5, lab.cex) dend ,- set(dend, labels_cex, 0.5) # And plot: par(mar = c(3,3,3,7)) plot(dend, main = ...
The inward rectifier K+ channels contain two putative membrane-spanning domains per subunit (M1, M2) and a pore (P) region, which is similar to the H5 domain of voltage-gated K+ channels. Here we have used Fourier transform infrared (FTIR) and CD spectroscopy to analyse the secondary structures of synthetic peptides corresponding to the M1, M2 and P regions of ROMK1 in aqueous solution, in organic solvents and in phospholipid membranes. A previous CD study was unable to provide any structural data on a similar P peptide [Ben-Efraim and Shai (1997) Biophys. J. 72, 85-96]. However, our FTIR and CD spectroscopic analyses indicate that this peptide adopts an α-helical structure when reconstituted into dimyristoyl phosphatidylcholine vesicles and lysophosphatidyl choline (LPC) micelles as well as in trifluoroethanol (TFE) solvent. This result is in good agreement with a previous study on a peptide corresponding to the pore domain of a voltage-gated K+ channel [Haris, Ramesh, Sansom, Kerr, Srai ...
Closure of ATP-regulated K(+) channels (K(ATP) channels) plays a central role in glucose-stimulated insulin secretion in beta cells. K(ATP) channels are also highly expressed in glucagon-producing alpha cells, where their function remains unresolved. Under hypoglycaemic conditions, K(ATP) channels are open in alpha cells but their activity is low and only ~1% of that in beta cells. Like beta cells, alpha cells respond to hyperglycaemia with K(ATP) channel closure, membrane depolarisation and stimulation of action potential firing. Yet, hyperglycaemia reciprocally regulates glucagon (inhibition) and insulin secretion (stimulation). Here we discuss how this conundrum can be resolved and how reduced K(ATP) channel activity, via membrane depolarisation, paradoxically reduces alpha cell Ca(2+) entry and glucagon exocytosis. Finally, we consider whether the glucagon secretory defects associated with diabetes can be attributed to impaired K(ATP) channel regulation and discuss the potential for remedial
Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ13 has a very low single channel conductance, low sensitivity to block by external barium and cesium, and no dependence of its inward rectification properties on the internal blocking particle magnesium. ...
1N9P: Structural Basis of Inward Rectification: Cytoplasmic Pore of the G Protein-Gated Inward Rectifier GIRK1 at 1.8 A Resolution
The capability of adapting cellular function and energy metabolism to varying physiological and pathological conditions is vitally important in animal cells. In the present work, we show that the Fox family may play a central role in expression of both molecular sensors of energy status and key regulatory genes of energy metabolism. First, in atrial cells, the expression of FoxO1, -O3, and -F2 cause increased expression of KATP channel subunits (the quintessential metabolic sensors7) and selective up- and downregulation of specific metabolic genes. A causal relationship between FoxO and KIR6.1 expression is demonstrated by electrophoretic mobility-shift assay and by experiments with siRNAs. Second, FoxO1, -O3, -F2, and -J2 are distributed unevenly within different cardiac chambers of the neonatal rat, in association with channel subunits KIR6.1, SUR1A, and SUR2B and 9 metabolic genes.42,43,50 Third, the periinfarcted zone of the rat left ventricle reveals an impressive plasticity of FoxO1, -O3, ...
This study is the first to demonstrate the critical role of a dystrophin isoform for the targeting and subcellular distribution of a potassium channel in glial cells. Our immunocytochemical and electrophysiological results demonstrate that functional expression of the dystrophin isoform Dp71 is necessary for the highly asymmetric expression of the inwardly rectifying potassium channel Kir4.1 in the main glial cell type in retina, the Müller cells.. Genetic inactivation of the weakly inwardly rectifying potassium channel Kir4.1 in mice demonstrated that this particular Kir subunit sets the membrane potential in Müller cells and underlies the main potassium conductance in these cells (Kofuji et al., 2000). Such marked asymmetric and clustered distribution of Kir4.1 subunits in these specialized glial cells has presumably the important physiological function of promoting the efficient buffering of extracellular potassium concentration in the retina (Newman et al., 1984). Although the cellular ...
Patients with permanent neonatal diabetes usually present within the first three months of life and need insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (KATP) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. Genotyping identifies the exact molecular etiology of early onset insulin requiring diabetes and has the potential to alter the management of the patient, who would otherwise be insulin dependent for life. Method: We identified a 6 year-old child who presented at 3 months of age with diabetic ketoacidosis. Blood samples for molecular genetic analysis were done. Results: The patient was diagnosed as a heterozygous for a missense mutation in the (KCNJ11) gene, for which she switched to sulphonylurea with a dose of 0.05 mg/kg/day. Conclusion: the need for medical practitioners to consider molecular testing for all patients
Predicted to have ATP-activated inward rectifier potassium channel activity. Predicted to be involved in potassium ion import across plasma membrane and regulation of ion transmembrane transport. Predicted to localize to plasma membrane. Used to study hypertrichotic osteochondrodysplasia Cantu type. Orthologous to human KCNJ8 (potassium inwardly rectifying channel subfamily J member 8 ...
Potassium channel openers (KCOs; e.g., P1075, pinacidil) exert their effects on excitable cells by opening ATP-sensitive potassium channels. These channels are heteromultimers composed with a 4:4 stoichiometry of an inwardly rectifying K+ channel subunit plus a regulatory subunit comprising the receptor sites for hypoglycemic sulfonylureas and KCOs (a sulfonylurea receptor). To elucidate stoichiometry of KCO action, we analyzed P1075 sensitivity of channels coassembled from sulfonylurea receptor isoforms with high or low P1075 affinity. Concentration activation curves for cDNA ratios of 1:1 or 1:10 resembled those for channel opening resulting from interaction with a single site, whereas models for activation requiring occupation of two, three, or four sites were incongruous. We conclude KCO-induced channel activation to be mediated by interaction with a single binding site per tetradimeric complex.. ...
Epilepsy, characterized by recurrent seizures, affects 1% of the general population. Interestingly, 25% of diabetics develop seizures with a yet unknown mechanism. Hyperglycemia downregulates inwardly rectifying potassium channel 4.1 (Kir4.1) in cultured astrocytes. Therefore, the present study aims to determine if downregulation of functional astrocytic Kir4.1 channels occurs in brains of type 2 diabetic mice and could influence hippocampal neuronal hyperexcitability. Using whole-cell patch clamp recording in hippocampal brain slices from male mice, we determined the electrophysiological properties of stratum radiatum astrocytes and CA1 pyramidal neurons. In diabetic mice, astrocytic Kir4.1 channels were functionally downregulated as evidenced by multiple characteristics including depolarized membrane potential, reduced barium-sensitive Kir currents and impaired potassium uptake capabilities of hippocampal astrocytes. Furthermore, CA1 pyramidal neurons from diabetic mice displayed increased spontaneous
TY - JOUR. T1 - Investigation of the subunit composition and the pharmacology of the mitochondrial ATP-dependent K+ channel in the brain. AU - Lacza, Zsombor. AU - Snipes, James A.. AU - Kis, Béla. AU - Szabó, Csaba. AU - Grover, Gary. AU - Busija, David W.. PY - 2003/12/19. Y1 - 2003/12/19. N2 - Selective activation of mitoKATP channels can protect the brain or cultured neurons against a variety of anoxic or metabolic challenges. However, little is known about the subunit composition or functional regulation of the channel itself. In the present study, we sought to characterize the mitoKATP channel in the mouse brain using overlapping approaches. First, we determined that mitochondria contain the pore-forming Kir6.1 and Kir6.2 subunits with Western blotting, immunogold electron microscopy and the identification of mitochondrial transport sequences. In contrast, we found no evidence for the presence of either known sulfonylurea receptors (SUR1 or SUR2) in the mitochondria. However, the ...
Context: ATP-sensitive potassium (KATP) stations regulate insulin secretion by coupling glucose rate of metabolism to β-cell membrane potential. gating properties of the producing channels were assessed biochemically and electrophysiologically. Results: Both E208K and V324M augment channel response to MgADP activation without altering level of sensitivity to ATP4? or sulfonylureas. Remarkably whereas E208K causes only a small increase in MgADP response consistent with the slight transient diabetes phenotype V324M causes a severe activating gating defect. Unlike E208K V324M also impairs channel expression in the cell surface which is definitely expected ON-01910 to dampen its practical impact on β-cells. When either mutation was combined with a mutation in the second nucleotide binding website of SUR1 previously shown to abolish Mg-nucleotide response the activating effect of E208K and V324M was also abolished. Moreover combination of E208K and V324M results in channels with Mg-nucleotide level ...
View mouse Kcnj16 Chr11:110968033-111027968 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression
View mouse Kcnj2 Chr11:111066164-111076821 with: phenotypes, sequences, polymorphisms, proteins, references, function, expression