Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells

Soejima, Mitsuhiro; Noma, Akinori

doi:10.1007/bf00587544

Cited by 424 publications

(246 citation statements)

References 28 publications

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“…Basal tone may be an important component of muscarinic (and other receptor) physiology. In fact, it has been shown that treatment of atrial cell membranes with muscarinic antagonists blocks spontaneous K + channel opening and G-protein activity [24,25]. Our observations imply that the control of G-protein expression may profoundly contribute to these phenomena.…”

Section: R ~ R* + G ~ R*g ---R Responsementioning

confidence: 57%

Constitutive activation of muscarinic receptors by the G‐protein G_q

et al. 1995

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In the absence of ligands, G-protein coupled receptors interconvert between active and inactive conformations. These conformations are stabilized by agonists and antagonists, respectively. Like agonists, G-proteins are thought to preferentially associate with receptors in the active conformation and should therefore be able to promote their formation in the absence of agonist. We show that over-expression of Gq induces constitutive activation of compatible muscarinic receptors and that this activity is blocked by muscarinic antagonists. Gq also increases the potency and efficacy of agonists. These results indicate that regulation of G-protein levels has a profound impact on receptor control of cellular physiology, even in the absence of agonist ligands.

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Section: R ~ R* + G ~ R*g ---R Responsementioning

confidence: 57%

Constitutive activation of muscarinic receptors by the G‐protein G_q

et al. 1995

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“…Also it remains unclear to what extent G proteins sustain a spontaneous agonist-independent activation under in vivo conditions. If not negligible, this basal G protein activation is likely to affect adenylyl cyclase and IK(ACh) Interestingly, it has been shown that single mAChR-activated K+ channels can open spontaneously even in the absence of mAChR stimulation (Soejima & Noma, 1984;Kaibara, Nakajima, Irisawa & Giles, 1991;Okabe et al 1991;Ito et al 1991) and that this spontaneous activity can be totally suppressed by pertussis toxin pretreatment (but see Kaibara et al 1991).…”

Section: Discussionmentioning

confidence: 99%

“…However, in a later study performed on isolated cardiac myocytes, atropine was also found to produce mAChR agonist-independent effects (Soejima & Noma, 1984) which could not be easily explained by a contamination by endogenous ACh. Indeed Soejima & Noma (1984) found that in isolated myocytes from rabbit atrium, atropine inhibits the spontaneous IK(ACh) single channel activity. However, this finding is contradicted by the observation that in guinea-pig atrial cells, basal activity of IK(ACh) channels was not affected by atropine (Okabe, Yatani & Brown, 1991).…”

Section: Introductionmentioning

confidence: 99%

Agonist‐independent effects of muscarinic antagonists on Ca2+ and K+ currents in frog and rat cardiac cells.

Hanf

Szabó

et al. 1993

The Journal of Physiology

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SUMMARY1. The whole-cell patch clamp and intracellular perfusion techniques were used for studying the effects of atropine and other muscarinic acetylcholine receptor (mAChR) antagonists on the L-type calcium currents ('Ca) in frog and rat ventricular myocytes, and on the mAChR-activated K+ current ('K(ACh)) in frog atrial myocytes.2. In frog ventricular myocytes, atropine (01 nm to I /,tM) reversed the inhibitory effect of acetylcholine (ACh, 1 nM) on 'Ca previously stimulated by isoprenaline (Iso, 2 JM), a /l-adrenergic agonist. However, in the concomitant presence of Iso, ACh and atropine, 'Ca was > 50 % larger than in Iso alone.3. The effects of atropine were then examined in the absence of mAChR agonists. 4. Atropine (1 M) had no effect on frog ICa (i) under basal conditions, (ii) upon stimulation of ICa by the dihydropyridine agonist (-)-Bay K 8644 (1 aM), or (iii) when ICa had been previously stimulated by intracellular perfusion with cyclic AMP (3 AM). However, atropine increased Jca after a stimulation by forskolin (0 3 1M).Therefore, an increased adenylyl cyclase activity was required for atropine to produce its stimulatory effect on Jca 5. The order of potency of mAChR antagonists to reverse the inhibitory effect of ACh on Iso elevated ICa in frog ventricle was atropine > AF-DX 116 > pirenzepine.In the absence of ACh, mAChR antagonists produced their stimulatory effect on Iso elevated ICa with the same order of potency.6. Intracellular substitution of Gpp(NH)p (5'-guanylylimidiphosphate) for GTP (420 AtM) induced a strong inhibition of frog Ica in the presence of Iso (2 aM).

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“…In earlier studies, the kinetic analysis of the muscarinic K+ channel openings in several mammalian species showed mean open times of -1 ms and the singlechannel conductances between 35-40 pS at symmetrical 140 mM-K' (Sakmann, Noma & Trautwein, 1983;Soejima & Noma, 1984;Kurachi et al 1986; Logothetis,134 D. KLiTI MUSCARINIC K+ CHANNEL MODULATION Kurachi, Galper, Neer & Clapham, 1987;Kim, Lewis, Graziadei, Neer, Bar-Sagi & Clapham, 1989). However, these studies have not examined the early activation of the K+ channel by ACh.…”

Section: Introductionmentioning

confidence: 95%

Modulation of acetylcholine‐activated K+ channel function in rat atrial cells by phosphorylation.

Kim

1991

The Journal of Physiology

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SUMMARY1. In voltage-clamped whole cells dialysed with GTP, extracellular application of ACh elicits an inwardly rectifying K+ current which subsequently decreases to a steady-state level well below the maximally induced current (desensitization). The mechanism of desensitization of the acetylcholine(ACh)-activated K+ channel current was studied in rat neonatal atrial cells at the single-channel level using the patch-clamp technique.2. In cell-attached patches with ACh in the pipette, a similar pattern of K+ channel current desensitization was present. Single-channel analyses revealed that the initial rapid decrease in channel activity was associated with progressive shortening of the mean open time (To) and prolongation of the mean closed time (rc) of the K+ channel.3. In excised, inside-out patches with ACh in the pipette, GTP activated K+ channels with a ro of 1.0 ms. Addition of ATP to the cytosolic surface resulted in progressive increases in To (from 1 to 5 ms) and channel activity. These changes are similar but opposite in direction to those observed during the early phase of AChinduced channel desensitization in cell-attached patches. 4. The effect of ATP on the channel kinetics was abolished in Mg2+-free solution AMP-PNP (adenylyl-imidodiphosphate, a non-hydrolysable analogue of ATP), ADP, CTP (cytidine triphosphate), ITP (inosine triphosphate) or UTP (uridine triphosphate) did not alter the channel kinetics, suggesting that the ATP effect on channel gating probably occurs via phosphorylation by a membrane-bound kinase. H-8 (an isoquinolinesulphonamide derivative which inhibits protein kinases A and C) failed to prevent the action of ATP on the channel.5. The increases in ro and channel activity produced by ATP could be completely reversed by an elevation of cytosolic [Ca21] to 3 x 10-5 M or above. 6. The effect of Ca21 on the ATP-induced changes in channel kinetics was blocked by sodium vanadate, a general phosphatase inhibitor. Okadaic acid, an inhibitor of protein phosphatase 1 and 2A, did not block the Ca2' effect. Calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1 -naphthalenesulphonamide (W-7), trifluoroperazine, and calmidazolium, partially blocked the effect of Ca2 .7. Alkaline phosphatase (20 units/ml) reversed the ATP-induced increases in T.MS 8700 and channel activitv. These results suggest that the ACh-activated K+ channel can be modulated by phosphorvlation and dephosphorylation.8. The early phase of desensitization of the K+ current activated by ACh can largely be explained by time-dependent changes in the open-and closed-time durations of the channel, possibly by activation of a Ca2+-calmodulin-dependent phosphatase. The secondary slower phase of desensitization was due to a progressive time-dependent decrease in the frequency of opening, and may involve effects on the receptor---G protein coupling.

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Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells

Cited by 424 publications

References 28 publications

Constitutive activation of muscarinic receptors by the G‐protein G_q

Constitutive activation of muscarinic receptors by the G‐protein G_q

Agonist‐independent effects of muscarinic antagonists on Ca2+ and K+ currents in frog and rat cardiac cells.

Modulation of acetylcholine‐activated K+ channel function in rat atrial cells by phosphorylation.

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Mode of regulation of the ACh-sensitive K-channel by the muscarinic receptor in rabbit atrial cells

Cited by 424 publications

References 28 publications

Constitutive activation of muscarinic receptors by the G‐protein Gq

Constitutive activation of muscarinic receptors by the G‐protein Gq

Agonist‐independent effects of muscarinic antagonists on Ca2+ and K+ currents in frog and rat cardiac cells.

Modulation of acetylcholine‐activated K+ channel function in rat atrial cells by phosphorylation.

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Constitutive activation of muscarinic receptors by the G‐protein G_q

Constitutive activation of muscarinic receptors by the G‐protein G_q