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Arrestin binding to the M₂ muscarinic acetylcholine receptor is precluded by an inhibitory element in the third intracellular loop of the receptor

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第13期275卷 9284-9289页

作者： Lee, KB Ptasienski, JA Pals-Rylaarsdam, R Gurevich, VV Hosey, MM Northwestern Univ Dept Mol Pharmacol & Biol Chem Chicago IL 60611 USA Northwestern Univ Inst Neurosci Chicago IL 60611 USA Sun Hlth Res Inst Ralph & Muriel Roberts Lab Vis Sci Sun City AZ 85732 USA

Desensitization of G protein-coupled receptors (GPCRs) involves the binding of members of the family of arrestins to the receptors, In the model system involving the visual GPCR rhodopsin, activation and phosphorylation of rhodopsin is thought to convert arrestin from a low to high affinity binding state. Phosphorylation of the M-2 muscarinic acetylcholine receptor (mAChR) has been shown to be required for binding of arrestins 2 and 3 in vitro and for arrestin-enhanced internalization in intact cells (Pals-Rylaarsdam, R., and Hosey, M. M. (1997) J. Biol. Chem. 272, 14152-14158), For the M, mAChR, arrestin binding requires phosphorylation at multiple serine and threonine residues at amino acids 307-311 in the third intracellular (i3) loop. Here, we have investigated the molecular basis for the requirement of receptor phosphorylation for arrestin binding. Constructs of arrestin 2 that can bind to other GPCRs in a phosphorylation independent manner were unable to interact with a mutant M, mAChR in which the Ser/Thr residues at 307-311 were mutated to alanines. However, although phosphorylation-deficient mutants of the M, mAChR that lacked 50-157 amino acids from the i3 loop were unable to undergo agonist-dependent internalization when expressed alone in tsA201 cells, co-expression of arrestin 2 or 3 restored agonist-dependent internalization. Furthermore, a deletion of only 15 amino acids (amino acids 304-319) was sufficient to allow for phosphorylation-independent arrestin-receptor interaction. These results indicate that phosphorylation at residues 307-311 does not appear to be required to activate arrestin into a high affinity binding state. Instead, phosphorylation at residues 307-311 appears to facilitate the removal of an inhibitory constraint that precludes receptor-arrestin association in the absence of receptor phosphorylation.

关键词：氨基酸序列抑制蛋白/代谢细胞系胞吞作用分子序列数据磷酰化蛋白质结合受体毒蕈碱M2 受体毒蕈碱/化学受体毒蕈碱/代谢人类

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Depolarization affects the binding properties of muscarinic acetylcholine receptors and their interaction with proteins of the exocytic apparatus

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第41期274卷 29519-29528页

作者： Ilouz, N Branski, L Parnis, J Parnas, H Linial, M Hebrew Univ Jerusalem Alexander Silberman Inst Life Sci Dept Biol Chem IL-91904 Jerusalem Israel Hebrew Univ Jerusalem Alexander Silberman Inst Life Sci Otto Loewi Ctr Mol & Cellular Neurobiol IL-91904 Jerusalem Israel

Membrane depolarization is the signal that triggers release of neurotransmitter from nerve terminals. As a result of depolarization, voltage-dependent Ca2+ channels open, level of intracellular Ca2+ increases. and release of neurotransmitter commences. Previous study had shown that in rat brain synaptosomes, muscarinic acetylcholine (ACh) receptors (mAChRs) interact with soluble NSF attachment protein receptor proteins of the exocytic machinery in a voltage-dependent manner. It was suggested that this interaction might control the rapid, synchronous release of acetylcholine, The present study investigates the mechanism for such a voltage-dependent interaction. Here we show that depolarization shifts mAChRs, specifically the m2 receptor subtype, to a low affinity state toward its agonists, At resting potential, mAChRs are in a high affinity state (K-d of similar to 20 nM) and they shift to a low affinity state (K-d of tens of mu M) upon membrane depolarization. In addition, interaction between m2 receptor subtype and the exocytic machinery increases with receptor occupancy. Both phenomena are independent of Ca2+ influx. We propose that these results may explain control of ACh release from nerve terminals. At resting potential the exocytic machinery is clamped due to its interaction with the occupied mAChR and depolarization relieves this interaction. This, together with Ca2+ influx, enables release of ACh to commence.

关键词：乙酰胆碱/代谢结合竞争性脑/代谢 CHO细胞钙/代谢卡巴胆碱/代谢仓鼠亚科胞吐作用膜电位膜蛋白质类/代谢毒蕈碱激动剂/药理学毒蕈碱拮抗剂/药理学 N-甲基东莨菪碱/代谢蛋白质结合 Qa-SNARE蛋白质类受体毒蕈碱/分类受体毒蕈碱/代谢突触体/代谢转染动物人类大鼠

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Muscarinic inhibitory and stimulatory regulation of the L-type Ca²⁺ current is not altered in cardiac ventricular myocytes from mice lacking endothelial nitric oxide synthase

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第2期528卷 279-289页

作者： Belevych, AE Harvey, RD Case Western Reserve Univ Dept Physiol & Biophys Cleveland OH 44106 USA

1. Using conventional and perforated patch-clamp techniques, the inhibitory and stimulatory effects of acetylcholine (ACh) on beta -adrenergic regulation of the L-type Ca2+ current (I-Ca) were studied in ventricular myocytes from wild-type mice (WT) and from mice lacking endothelial nitric oxide synthase (eNOS, or NOS3;NOS3-KO mice). 2. To validate the direct comparison of ACh effects on beta -adrenergic responses, the sensitivity of I-Ca to the beta -adrenergic agonist isoprenaline (Iso) was studied in both WT and NOS3-KO mouse myocytes. I-Ca sensitivity to Iso was not found to be significantly different in WT and NOS3-KO myocytes: Iso increased I-Ca with an EC50 of 4.9 and 3.7 nM in WT and NOS3-KO myocytes, respectively. 3. ACh-induced inhibition of I-Ca did not significantly differ in ventricular myocytes from WT and NOS3-KO mice. ACh (10 muM) inhibited the stimulatory effect of 3 nM Iso by 39 and 35% in WT and NO83-KO myocytes, respectively. 4. Exposure to and subsequent washout of ACh in the continuous presence of submaximally stimulating concentrations of Iso (1-3 nM) resulted in a transient rebound stimulation of I-Ca in both WT and NOS3-KO mouse myocytes. The magnitude of the stimulatory effect of ACh did not significantly differ in WT and NOS3-KO mice. 5. These results indicate that nitric oxide (NO) generated by NOS3 does not significantly affect the beta -adrenergic responsiveness of I-Ca. The results also confirm previous work indicating that NO generated by NOS3 is not obligatory for muscarinic inhibition of the beta -adrenergically regulated I-Ca in ventricular myocytes. Finally these results demonstrate for the first time that NO generated by NOS3 is not involved in muscarinic rebound stimulation of I-Ca in ventricular myocytes.

关键词：乙酰胆碱/药理学肾上腺素能β激动剂/药理学钙通道 L型/药物作用钙通道 L型/代谢心室/细胞学心室/药物作用心室/代谢异丙肾上腺素/药理学小鼠近交C57BL 小鼠基因敲除心肌/细胞学心肌/代谢一氧化氮合酶/缺乏一氧化氮合酶/遗传学一氧化氮合酶/代谢一氧化氮合酶Ⅱ型一氧化氮合酶Ⅲ型膜片钳术受体毒蕈碱/药物作用受体毒蕈碱/代谢动物小鼠

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Identification of Gβγ binding sites in the third intracellular loop of the M₃-muscarinic receptor and their role in receptor regulation

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JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第12期275卷 9026-9034页

作者： Wu, GY Bogatkevich, GS Mukhin, YV Benovic, JL Hildebrandt, JD Lanier, SM Med Univ S Carolina Dept Pharmacol Charleston SC 29425 USA Med Univ S Carolina Div Nephrol Charleston SC 29425 USA Thomas Jefferson Univ Kimmel Canc Inst Dept Microbiol & Immunol Philadelphia PA 19107 USA

G beta gamma binds directly to the third intracellular (i3) loop subdomain of the M-3-muscarinic receptor (RIPE), In this report, we identified the G beta gamma binding motif and G-protein-coupled receptor kinase (GRK2) phosphorylation sites in the M-3-MR i3 loop via a strategy of deletional and site-directed mutagenesis. The G beta gamma binding domain was localized to Cys(289)-His(330) within the M-3-MR-Arg(252)Gin(490) i3 loop, and the binding properties (affinity, influence of ionic strength) of the M-3-MR-Cys(289)-Ris(330) i3 loop subdomain were similar to those observed for the entire i3 loop. Site-directed mutagenesis of the M-3-MR-Cys(289)-His(330) i3 loop subdomain indicated that Phe(312) Phe(314) and a negatively charged region (Glu(324)-Asp(329)) were required for interaction with G beta gamma, Generation of the full-length M-3-MR-Arg(252)-Gln(490) i3 peptides containing the F312A mutation mere also deficient in G beta gamma binding and exhibited a reduced capacity for phosphorylation by GRK2. A similar, parallel strategy resulted in identification of major residues ((SSS333)-S-331 (318)SASS(351)) phosphorylated by GRK2, which were just downstream of the G beta gamma binding motif, Full-length M-3-MR constructs lacking the 42-amino acid G beta gamma binding domain (Cys(289)-His(330)), containing the F312A mutation exhibited ligand recognition properties similar to wild type receptor and also effectively mediated agonist-induced increases in intracellular calcium following receptor expression in Chinese hamster ovary and/or COS 7 cells. However, the M-3-MR Delta Cys(289)-His(330) and M-3-MR(F312A) constructs mere deficient in agonist-induced sequestration, indicating a key role for the G beta gamma-MR i3 loop interaction in receptor regulation and signal processing.

关键词：氨基酸序列结合部位生物转运环AMP依赖性蛋白激酶类/代谢 GTP结合蛋白质β亚单位 GTP结合蛋白质γ亚单位 GTP结合蛋白质类/遗传学 GTP结合蛋白质类/代谢异源三聚体GTP结合蛋白质类分子序列数据诱变定点肽碎片/代谢磷酰化受体毒蕈碱M3 受体毒蕈碱/遗传学受体毒蕈碱/代谢重组蛋白质类/代谢丝氨酸/代谢信号传导 β肾上腺素能受体激酶类

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M₃ muscarinic acetylcholine receptors regulate cytoplasmic myosin by a process involving RhoA and requiring conventional protein kinase C isoforms

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第26期274卷 18675-18685页

作者： Strassheim, D May, LG Varker, KA Puhl, HL Phelps, SH Porter, RA Aronstam, RS Noti, JD Williams, CL Guthrie Res Inst Mol Pharmacol Lab Sayre PA 18840 USA Guthrie Res Inst Neurobiol Lab Sayre PA 18840 USA Guthrie Res Inst Mol Biol Lab Sayre PA 18840 USA Guthrie Clin Dept Surg Sayre PA 18840 USA

Although muscarinic acetylcholine receptors (mAChR) regulate the activity of smooth muscle myosin, the effects of mAChR activation on cytoplasmic myosin have not been characterized. We found that activation of transfected human M-3 mAChR induces the phosphorylation of myosin light chains (MLC) and the formation of myosin-containing stress fibers in Chinese hamster ovary (CHO-m3) cells. Direct activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) also induces myosin light chain phosphorylation and myosin reorganization in CHO-m3 cells. Conventional (alpha), novel (delta), and atypical (iota) PKC isoforms are activated by mAChR stimulation or PMA treatment in CHO-m3 cells, as indicated by PKC translocation or degradation. mAChR-mediated myosin reorganization is abolished by inhibiting conventional PKC isoforms with Go6976 (IC50 = 0.4 mu M), calphostin C (IC50 = 2.4 mu M), or chelerythrine (IC50 = 8.0 mu M) Stable expression of dominant negative RhoA(Asn-19) diminishes, but does not abolish, mAChR-mediated myosin reorganization in the CHO-m3 cells. Similarly, mAChR-mediated myosin reorganization is diminished, but not abolished, in CHO-m3 cells which are multi-nucleate due to inactivation of Rho with C3 exoenzyme, Expression of dominant negative RhoA(Asn-19) Or inactivation of RhoA with C3 exoenzyme does not affect PMA-induced myosin reorganization. These findings indicate that the PKC-mediated pathway of myosin reorganization (induced either by M-3 mAChR activation or PMA treatment) can continue to operate even when RhoA activity is diminished in CHO-m3 cells. Conventional PKC isoforms and RhoA may participate in separate but parallel pathways induced by M-3 mAChR activation to regulate cytoplasmic myosin, Changes in cytoplasmic myosin elicited by M-3 mAChR activation may contribute to the unique ability of these receptors to regulate cell morphology, adhesion, and proliferation.

关键词： ADP核糖转移酶类/代谢肉毒毒素类 CHO细胞卡巴胆碱/药理学仓鼠亚科细胞质/代谢 GTP结合蛋白质类/代谢同工酶类/代谢肌球蛋白类/代谢蛋白激酶C/代谢受体毒蕈碱M1 受体毒蕈碱M3 受体毒蕈碱/代谢十四酰佛波乙酯/药理学 ρAGTP结合蛋白质动物人类

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Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第26期96卷 15292-15297页

作者： Xie, LH Horie, M Takano, M Kyoto Univ Grad Sch Med Dept Physiol & Biophys Kyoto 6068501 Japan Kyoto Univ Grad Sch Med Dept Cardiovasc Med Kyoto 6068501 Japan

In the COS7 cells transfected with cDNAs of the Kir6.2, SUR2A, and M-1 muscarinic receptors, we activated the ATP-sensitive potassium (K-ATP) channel with a K+ channel opener and recorded the whole-cell KATP current. The KATP current was reversibly inhibited by the stimulation of the M-1 receptor, which is linked to phospholipase C (PLC) by the G(q) protein. The receptor-mediated inhibition was observed even when protein kinase C (PKC) was inhibited by H-7 or by chelating intracellular Ca2+ with 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate (BAPTA) included in the pipette solution. However, the receptor-mediated inhibition was blocked by U-73122, a PLC inhibitor. M-1-receptor stimulation failed to inhibit the K-ATP current activated by the injection of exogenous phosphatidylinositol 4,5-bisphosphate (PIP2) through the whole-cell patch pipette. The receptor-mediated inhibition became irreversible when the replenishment of PIP2 was blocked by wortmannin (an inhibitor of phosphatidylinositol kinases), or by including adenosine 5'-[beta,gamma-imido]triphosphate (AMPPNP, a nonhydrolyzable ATP analogue) in the pipette solution. In inside-out patch experiments, the ATP sensitivity of the K-ATP channel was significantly higher when the M-1 receptor in the patch membrane was stimulated by acetylcholine. The stimulatory effect of pinacidil was also attenuated under this condition. We postulate that stimulation of PLC-linked receptors inhibited the K-ATP channel by increasing the ATP sensitivity, not through PKC activation, but most probably through changing PIP2 levels.

关键词： 1-(5-异喹啉磺酰基)-2-甲基哌嗪/药理学乙酰胆碱/代谢腺苷三磷酸/药理学剂量效应关系药物导电性雌烯类/药理学鸟苷二磷酸/类似物和衍生物鸟苷二磷酸/药理学磷脂酰肌醇4 5-二磷酸/代谢钾通道/代谢钾通道内向整流蛋白激酶C/代谢吡咯烷酮类/药理学受体毒蕈碱M1 受体毒蕈碱/代谢硫代核苷酸类/药理学 C型磷脂酶类/代谢

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6β-acyloxy(nor)tropanes:: Affinities for antagonist/agonist binding sites on transfected and native muscarinic receptors

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第13期43卷 2514-2522页

作者： Daly, JW Gupta, TH Padgett, WL Pei, XF NIDDK Bioorgan Chem Lab NIH Bethesda MD 20892 USA

A series of esters of 6 beta-hydroxynortropane and the N-methyl analogue 6 beta-tropanol were synthesized and screened versus binding of an antagonist (quinuclidinyl benzilate) and an agonist (oxotremorine-M) at sites on human m(1)-, m(2)-, m(3)-, and m(4)-muscarinic receptors in transfected cell membranes and on native M-1-muscarinic receptors in rat brain membranes and native M-2-muscarinic receptors in rat heart membranes. Most 6 beta-acyloxy(nor)tropanes had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at transfected m(1)- and native M-1-receptors, indicative of agonist activity. 6 beta-Acetoxynortropane had K-i values versus oxotremorine-M binding at m(1)-, m(2)-, and m(4)-receptors ranging from 4 to 7 nM. N-Methylation reduced affinity greatly as did increasing the size of the acyl moiety. The affinity of 6 beta-benzoyloxynortropane and other analogues with larger acyl moieties was little affected by N-methylation or in some cases was increased. 6 beta-Acyloxy(nor)tropanes and classical muscarinic agonists, such as muscarine and oxotremorine, had higher affinity versus oxotremorine-M binding compared to quinuclidinyl benzilate binding at native M-2-muscarinic receptors of heart, but not at transfected m(2)-muscarinic receptors. Antagonist/agonist binding ratios were not obtained for transfected m(3)-receptors, since significant oxotremorine-M binding could not be detected. 6 beta-Acyloxy(nor)tropane, two other (nor)tropanes, and the classical muscarinic agonists had higher affinity versus agonist binding compared to antagonist binding for transfected m(4)-receptors. The antagonist/agonist binding ratio method is clearly not always reliable for predicting agonist activity at muscarinic receptors.

关键词：结合部位 CHO细胞大脑皮质/代谢仓鼠亚科毒蕈碱激动剂/化学合成毒蕈碱激动剂/化学毒蕈碱激动剂/代谢毒蕈碱激动剂/药理学心肌/代谢氧代震颤素/类似物和衍生物氧代震颤素/代谢奎宁环苯齐酸盐/代谢受体毒蕈碱M1 受体毒蕈碱M2 受体毒蕈碱M3 受体毒蕈碱M4 受体毒蕈碱/药物作用受体毒蕈碱/代谢转染托烷类/化学合成托烷类/化学托烷类/代谢托烷类/药理学动物人类大鼠

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Muscarinic M₃ receptor inactivation reveals a pertussis toxin-sensitive contractile response in the guinea pig colon:: Evidence for M₂/M₃ receptor interactions

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第1期289卷 464-476页

作者： Sawyer, GW Ehlert, FJ Univ Calif Irvine Coll Med Dept Pharmacol Irvine CA 92697 USA

The role of M-2 and M-3 receptors in the contractile and phosphoinositide responses elicited to oxotremorine-M was investigated in the guinea pig colon. Under standard conditions, both the contractile and phosphoinositide responses were insensitive to pertussis toxin and irreversibly antagonized by alkylation of M-3 receptors with N-(2-chloroethyl)-4-piperidinyl diphenylacetate. After treatment with N-(2-chloroethyl)-4-piperidinyl diphenylacetate, the remaining contractile response was sensitive to pertussis toxin and weakly antagonized by the M-2- and M-4-selective antagonist AF-DX 116. In contrast, the residual phosphoinositide response was unaffected by pertussis toxin. The pertussis toxin sensitivity of the remaining contractile response suggests that the M-2 receptor is mediating the contraction, whereas its weak antagonism by AF-DX 116 suggests that an alternate muscarinic subtype mediates the response. To explain this enigma, we investigated a mathematical model for receptor action based on an interaction between two receptor subtypes (M-2 and M-3). This model predicts that a response mediated by both the M-2 and M-3 receptor can be pertussis toxin sensitive yet exhibit an antagonistic profile indicative of an M-3 response.

关键词：结肠/药物作用结肠/生理学二苯乙酸类/药理学水解作用模型生物学毒蕈碱激动剂/药理学毒蕈碱拮抗剂/药理学肌收缩/药物作用肌平滑/药物作用肌平滑/生理学氧代震颤素/类似物和衍生物氧代震颤素/药理学百白咳毒素磷脂酰肌醇类/代谢哌啶类/药理学哌仑西平/类似物和衍生物哌仑西平/药理学受体毒蕈碱M2 受体毒蕈碱M3 受体毒蕈碱/药物作用受体毒蕈碱/代谢毒力因子鲍特菌属/药理学动物豚鼠男(雄)性

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Slow modal gating of single G protein-activated K⁺ channels expressed in Xenopus oocytes

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期524卷 737-755页

作者： Yakubovich, D Pastushenko, V Bitler, A Dessauer, CW Dascal, N Tel Aviv Univ Sackler Sch Med Dept Physiol & Pharmacol IL-69978 Ramat Aviv Israel Univ Linz Inst Biophys A-4040 Linz Austria Univ Texas Sch Med Dept Integrat Biol Pharmacol & Physiol Houston TX 77030 USA

1. The slow kinetics of G protein-activated K+ (GIRK) channels expressed in Xenopus oocytes were studied in single-channel, inside-out membrane patches. Channels formed by GIRK1 plus GIRK4 subunits, which are known to form the cardiac acetylcholine (ACh)-activated GIRK channel (K-ACh), were activated by a near-saturating dose of G protein beta gamma subunits (G(beta gamma);20 nM). 2. The kinetic parameters of the expressed GIRK1/4 channels were similar to those of cardiac K-ACh. GIRK1/4 channels differed significantly from channels for med by GIRK1 with the endogenous oocyte subunit GIRK5 (GIRK1/5) in some of their kinetic parameters and in a 5-fold lower open probability, P-o. The unexpectedly low P-o (0.025) of GIRK1/4 was due to the presence of closures of hundreds of milliseconds;the channel spent similar to 90 % of the time in the long closed states. 3. GIRK1/4 channels displayed a clear modal behaviour: on a time scale of tens of seconds, the G(beta gamma)-activated channels cycled between a low-P-o mode (P-o of about 0.0034) and a bursting mode characterized by an similar to 30-fold higher P-o and a different set of kinetic constants (and, therefore, a different set of channel conformations). The available evidence indicates that the slow model transitions are not driven by binding and unbinding of G(beta gamma). 4. The GTP gamma S-activated G(alpha I1) subunit, previously shown to inhibit GIRK channels, substantially increased the time spent in closed states and apparently shifted the channel to a mode similar, but not identical, to the low-P-o mode. 5. This is the first demonstration of slow modal transitions in GIRK channels. The detailed description of the slow gating kinetics of GIRK1/4 may help in future analysis of mechanisms of GIRK gating.

关键词：克隆分子 G蛋白偶联内向整流钾通道 GTP结合蛋白质α亚单位 Gi-Go/代谢基因表达/生理学鸟苷5'-O-(3-硫代三磷酸)/药理学离子通道闸门/药物作用离子通道闸门/生理学动力学膜电位/药物作用膜电位/生理学心肌/化学卵母细胞/生理学膜片钳术质粒钾通道/遗传学钾通道/代谢钾通道内向整流 RNA 信使/药理学受体毒蕈碱/遗传学受体毒蕈碱/代谢爪蟾光滑动物女(雌)性

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Lack of effect of McN-A-343 on membrane current and contraction in guinea pig ventricular myocytes

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 1999年第2期290卷 641-648页

作者： Shen, JB Jiang, B Pappano, AJ Univ Connecticut Ctr Hlth Dept Pharmacol Farmington CT 06030 USA

We asked whether agonist occupancy of M-1 muscarinic receptor (mAChR) causes increased L-type Ca2+ [I-Ca(L)] and contractions in ventricular myocytes. Voltage-clamp pulses evoked I-Ca(L) in guinea pig ventricular myocytes superfused with Ty rode's solution (22-24 degrees C). The mAChR agonists carbachol (Cch, nonselective), McN-A-343 (McN, M-1-selective), and oxo otremorine (Oxo, M-2-selective) were tested at 0.1 mM. None of these agonists affected basal I-Ca(L). McN did not change isoproterenol-stimulated I-Ca(L) in 13 of 15 cells. The slight decrease in two cells was not muscarinic because atropine (1 mu M) did not antagonize it. Carbachol or Oxo decreased isoproterenol-stimulated I-Ca(L) by 87 +/- 6.7 (n = 8 cells) and 49 +/- 9.0% (n = 4 cells), respectively. Atropine blocked inhibition by Cch or Oxo. External stimulation evoked contractions of single myocytes (35 degrees C). McN increased contraction in 1 of 22 cells stimulated at 0.2 Hz and in 0 of 16 cells stimulated at 1.0 Hz. Carbachol significantly increased contraction in 10 of 15 cells at 0.2 Hz and in 8 of 10 cells at 1.0 Hz stimulus frequency. Summarily, the M-1-selective agonist McN had a negligible role to regulate I-Ca(L). The antiadrenergic effect of mAChR agonists is attributable to M-2 receptor occupancy. That Cch, but not McN, increased cell shortening excludes participation of M-1 mAChR in the stimulant effect of Cch on guinea pig ventricular myocyte contractions.

关键词：肾上腺素能β激动剂/药理学钙通道/代谢钙通道 L型卡巴胆碱/药理学细胞膜/药物作用细胞膜/代谢环AMP/代谢电生理学心脏/药物作用心室/细胞学心室/药物作用异丙肾上腺素/药理学毒蕈碱激动剂/药理学心肌收缩/药物作用氧代震颤素/药理学膜片钳术受体毒蕈碱M1 受体毒蕈碱M2 受体毒蕈碱/药物作用受体毒蕈碱/代谢动物豚鼠

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