Atypical beta-adrenoceptors, different from beta 3-adrenoceptors and probably from the low-affinity state of beta 1-adrenoceptors, relax the rat isolated mesenteric artery.
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(1) We examined whether beta3- and/or atypical beta-adrenoceptors relax the rat isolated mesenteric artery. (2) Mesenteric arteries precontracted with phenylephrine were relaxed by beta-agonists with the following potencies (pD2): nonselective agonist isoprenaline (6.00)>nonconventional partial agonist cyanopindolol (5.45)>beta2-agonist fenoterol (4.98)>nonconventional partial agonist CGP 12177 (4.19)>beta3-agonist ZD 2079 (3.72). The beta3-agonist CL 316243 1 mm relaxed the vessel only marginally. (3) The concentration-response curves (CRCs) for cyanopindolol, CGP 12177 and ZD 2079 were not affected by the nonselective beta-antagonist propranolol 0.3 microm, the beta2-antagonist ICI 118551 1 microm and by CL 316243 60 microm, but shifted to the right by bupranolol (pA2 5.3-5.7), CGP 20712 (5.4) and SR 59230A (6.5-6.7) (the latter three drugs block atypical and/or beta3-adrenoceptors at high concentrations). (4) The CRC for isoprenaline was shifted to the right by propranolol (pA2 7.0) but, in the presence of propranolol 0.3 microm, not affected by SR 59230A 1 microm. The CRC for fenoterol was shifted to the right by propranolol (pA2 6.9) and ICI 118551 (6.8). (5) Removal of endothelium diminished the vasorelaxant effects of cyanopindolol, CGP 12177 and ZD 2079. (6) Fenoterol and cyanopindolol also relaxed (endothelium-intact) mesenteric arteries precontracted with serotonin. The relaxant effect of cyanopindolol was antagonized by bupranolol to about the same degree as in phenylephrine-contracted vessels. (7) In conclusion, beta2- and atypical beta-adrenoceptors (but not beta3-adrenoceptors) relax the rat mesenteric artery. The atypical beta-adrenoceptor, which is partially located endothelially, may differ from the low-affinity state of the beta1-adrenoceptor. (+info)
Attenuation of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced rhabdomyolysis with alpha1- plus beta3-adrenoreceptor antagonists.
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1. Studies were designed to examine the effects of alpha(1) (alpha(1)AR)- plus beta(3)-adrenoreceptor (beta(3)AR) antagonists on 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced hyperthermia and measures of rhabdomyolysis (creatine kinase (CK)) and renal function (blood urea nitrogen (BUN) and serum creatinine (sCr)) in male Sprague-Dawley rats. 2. MDMA (40 mg x kg(-1), s.c.) induced a rapid and robust increase in rectal temperature, which was significantly attenuated by pretreatment with the alpha(1)AR antagonist prazosin (100 microg x kg(-1), i.p.) plus the beta(3)AR antagonist SR59230A (5 mg x kg(-1), i.p.). 3. CK levels significantly increased (peaking at 4 h) after MDMA treatment and were blocked by the combination of prazosin plus SR59230A. 4. At 4 h after MDMA treatment, BUN and sCr levels were also significantly increased and could be prevented by this combination of alpha(1)AR- plus beta(3)AR-antagonists. 5. The results from this study suggest that alpha(1)AR and beta(3)AR play a critical role in the etiology of MDMA-mediated hyperthermia and subsequent rhabdomyolysis. (+info)
Structure and function of beta3-adrenergic receptors.
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Beta-adrenergic receptors have been subdivided into three types: beta1-, beta2- and beta3-adrenergic receptors. beta1-adrenergic receptors are predominant in the heart, beta2-adrenergic receptors--in the respiratory system, and beta3-adrenergic receptors--in the adipose tissues. However, since 1989, when beta3-adrenergic receptor was cloned, numerous biochemical and functional studies have confirmed its presence in various species and tissues, including the heart. Unlike beta1- and beta2-adrenergic receptors, it has been shown that beta3-adrenergic receptors possess the cardiodepressant effects in human ventricles, what did not fit to its stimulatory properties of adenylyl cyclase in other tissues. In this regard, the role of beta3-adrenergic receptors in the regulation of cardiac function may be of great importance in pathological conditions and remains undetermined, so far. In this review brief characterization of beta3-adrenergic receptors, concerning their structure, function and possible pathophysiological role is provided. (+info)
Evidence for pleiotropic signaling at the mouse beta3-adrenoceptor revealed by SR59230A [3-(2-Ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate].
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This study examines the action of the beta(3)-adrenoceptor antagonist SR59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanoloxal ate] at cloned mouse beta(3)-adrenoceptors expressed in Chinese hamster ovary cells (CHO-K1-beta(3)) or endogenously expressed in 3T3-F442A adipocytes or ileum. SR59230A displayed partial agonist properties compared with the beta(3)-adrenoceptor agonist CL316243 [(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2 ,2-dicarboxylate] in CHO-K1-beta(3) with the intrinsic activity increasing with the level of receptor expression. Functional affinity values for SR59230A at each level of receptor expression were in agreement with pK(I) values determined by binding. In cytosensor microphysiometer studies, SR59230A was a full agonist for increases in extracellular acidification rates (ECARs) at all levels of receptor expression, and antagonist actions were measurable only in medium- or low-expressing cells. In 3T3-F442A adipocytes, SR59230A antagonized CL316243-mediated increases of cAMP and had no agonist actions. However, in the cytosensor micro-physiometer, SR59230A (acting via beta(3)-adrenoceptors) was an agonist with an intrinsic activity greater than CL316243. In mouse ileum, SR59230A relaxed smooth muscle, although concentration-response curves were biphasic. Relaxant effects were produced by concentrations that did not affect cAMP levels. Differences in tissue responses to SR59230A were not caused by major differences in expression of Galphas. ECAR responses were not affected by pretreatment of cells with pertussis toxin, indicating that signaling did not involve Gi. Therefore, SR59230A displays agonist and antagonist actions at the mouse beta(3)-adrenoceptor. Because SR59230A only antagonized accumulation of cAMP in 3T3-F442A adipocytes yet in the same cells was an agonist for ECAR, cAMP-independent signaling pathways must mediate part of the agonist actions in the microphysiometer. (+info)
Evidence for a secondary state of the human beta3-adrenoceptor.
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There are three members of the beta-adrenoceptor family, all of which are primarily coupled to G(s) proteins. Recent studies using the huge range of beta-ligands now available have given remarkable new insights into their pharmacology. beta1-adrenoceptors exist in at least two active conformations, whereas beta2-adrenoceptors are able to induce signaling via different agonist-induced receptor conformational states, and their affinity for antagonists can be altered by highly efficacious agonists. This study therefore examined the pharmacology of the human beta3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as beta-antagonists have agonist properties at the beta3-adrenoceptor. Antagonist affinity measurements varied at the beta3-adrenoceptor in a manner similar to those observed at human beta1-adrenoceptors and unlike those seen at beta2-adrenoceptors. Some ligands (e.g., fenoterol and cimaterol) were more readily inhibited by all antagonists, whereas other ligands [e.g., alprenolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propa nol hydrochloride [SR 59230A]) stimulated responses that were more resistant to antagonism. Alprenolol inhibited fenoterol-induced beta3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the beta3-adrenoceptor. (S)-4-[2-Hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide (ZD 7114) stimulated a two-component response, of which the first component was more readily antagonized than the second. Taken together, these experiments suggest that the human beta3-adrenoceptor exists in at least two different agonist conformations with a similar high- and low-affinity pharmacology analogous to, if not as pronounced as, the beta1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human beta3-adrenoceptor seems similar to the human beta1-adrenoceptor. (+info)
Functional domains of the mouse beta3-adrenoceptor associated with differential G protein coupling.
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Alternative splicing of mouse beta3-adrenoceptor transcripts produces an additional receptor isoform (beta3b-adrenoceptor) with a C terminus comprising 17 amino acids distinct from the 13 in the known receptor (beta3a-adrenoceptor). We have shown that the beta3b-adrenoceptor couples to both Gs and Gi, whereas the beta3a-adrenoceptor couples only to Gs. To define the regions involved in this differential G protein coupling, we have compared wild-type, truncated, and mutant beta3-adrenoceptors. In Chinese hamster ovary cells expressing beta3-adrenoceptors truncated at the splicing point, cAMP accumulation with CL316243 [(R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2 ,2-dicarboxylate] increased by 59% following pretreatment with pertussis toxin, suggesting that the C-terminal region of the beta3a-adrenoceptor inhibits coupling to Gi. We next utilized the cell-penetrating peptide Transportan 10 (Tp10) to introduce peptides comprising the different C-terminal tail fragments into cells expressing beta3a-adrenoceptor, beta3b-adrenoceptor, and the truncated beta3-adrenoceptor. Treatment with beta3a-Tp10 (1 microM) caused cAMP responses to CL316243 in the beta3a-adrenoceptor to become pertussis toxin-sensitive and display a 30% increase over control, whereas the other peptides did not affect any receptor. Mutation at a potential tyrosine phosphorylation site (Tyr392Ala beta3a-adrenoceptor) did not alter responses or pertussis toxin sensitivity relative to the parent receptor. Surprisingly, a Ser388Ala/Ser389Ala mutant beta3b-adrenoceptor became unresponsive to CL316243 while retaining an extracellular acidification rate response to SR59230A [3-(2-ethylphenoxy)-1-[(1,S)-1,2,3,4-tetrahydronapth-1-ylamino]-2S-2-propanol oxalate]. Our findings suggest that the beta3a-adrenoceptor cannot couple to Gi because of conformational changes induced by a protein(s) that interacts with residues in the C-terminal tail or because this protein(s) affects the intracellular localization of the beta3a-adrenoceptor. (+info)
Effect of adipocyte beta3-adrenergic receptor activation on the type 2 diabetic MKR mice.
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The antiobesity and antidiabetic effects of the beta3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a beta3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that beta3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for beta3-adrenergic agonists in nonobese diabetic subjects. (+info)
Ligand-directed signaling: 50 ways to find a lover.
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In contrast to earlier concepts, it seems that distinct ligands acting on the same receptor may elicit qualitative different response patterns, a phenomenon given many names, including "functional selectivity," "agonist-directed trafficking," "biased agonism," "protean agonism," or "ligand-directed signaling." In this issue of Molecular Pharmacology, Sato et al. (p. 1359) extend this concept to beta(3)-adrenergic receptors and report that distinct ligands can activate a single distal response via different signaling pathways. Moreover, they demonstrate that expression density can affect how distinct ligands acting on the same receptor differentially induce cellular responses. We discuss the underlying concepts for such findings and their implications for drug discovery. (+info)