Phosphorylation of brain muscarinic receptor: Evidence of receptor regulation

Ho, Andrew K.S.; Ling, Qilang; Duffield, Rose; Lam, Philip Y.; Wang, Lerry H.

doi:10.1016/0006-291x(87)91500-2

Cited by 22 publications

(8 citation statements)

References 11 publications

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“…If phosphorylation of muscarinic receptors and/or G proteins brings about desensitization via reduction in the affinity of carbachol for muscarinic receptors and uncoupling between muscarinic receptors and G proteins in our muscle preparation, the transient resensitization might be induced by de-phosphorylation of phosphorylated muscarinic receptors by means of protein phosphatases. Phosphorylated muscarinic receptors are dephosphorylated in various tissues in vitro by calcineurin (Ho et al, 1987;Rosenbaum et al, 1987) or acid phosphatase , but not by alkaline phosphatase (Rosenbaum et al, 1987). Because of shortage of muscarinic receptors in our membrane preparation such phosphorylation/dephosphorylation has not been elucidated in relation to desensitization/resensitization.…”

Section: Discussionmentioning

confidence: 96%

“…Ml or M2 muscarinic receptor subtypes are phosphorylated in various tissues in vitro by protein kinase A (Ho et al, 1987;Rosenbaum et al, 1987), protein kinase C , BARK (Kwatra et al, 1989a) or a BARK-like kinase (Haga & Haga, 1989). The muscarinic stimulation induces phosphorylation of muscarinic receptors in vivo (Kwatra & Hosey, 1986;Kwatra et al, 1987;1989b).…”

Section: Discussionmentioning

confidence: 99%

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Novel regulation of muscarinic receptors and their coupling with G proteins in smooth muscle: transient resensitization during desensitizing process

Hishinuma

Matsumoto

Uchida

et al. 1993

British J Pharmacology

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6 These results indicate that the whole process of desensitization, resensitization and re-desensitization are related to changes in the binding ability of muscarinic receptors, in their coupling with G proteins and in the post-receptor steps of the signal transduction. We emphasize that the desensitizing process involves an early transient phase of resensitization that could be caused by restoration of both the affinity of carbachol for muscarinic receptors and their coupling with G proteins. This novel resensitization mechanism may have some physiological significance for gellular homoeostasis by modulating cellular responsiveness transiently or even in an oscillatory manner during the process of desensitization.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Novel regulation of muscarinic receptors and their coupling with G proteins in smooth muscle: transient resensitization during desensitizing process

Hishinuma

Matsumoto

Uchida

et al. 1993

British J Pharmacology

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“…Recently phosphorylation of receptors, including a,(Leeb- Lundberg et al, 1985) and fi-adrenoceptors (Sibley & Lefkowitz, 1985) and nicotinic (Huganir et al, 1986) and muscarinic cholinoceptors (Kwatra & Hosey, 1986;Ho et al, 1987), has been thought to be involved in desensitization. Ho et al, (1987) found that phosphorylation of muscarinic ACh receptors was accompanied with a loss in specific binding to [3H]-QNB.…”

Section: Discussionmentioning

confidence: 99%

“…Ho et al, (1987) found that phosphorylation of muscarinic ACh receptors was accompanied with a loss in specific binding to [3H]-QNB. On the other hand, Kwatra & Hosey (1986) reported that phosphorylation of muscarinic ACh receptors was not accompanied by a reduction in muscarinic ACh receptor protein but a decrease in affinity of the receptor for the agonist.…”

Section: Discussionmentioning

confidence: 99%

The change in the threshold for short‐term desensitization in isolated smooth muscle cells showing an all‐or‐none response to acetylcholine

Mita

Uchida

1991

British J Pharmacology

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1 Isolated smooth muscle cells from guinea-pig taenia caecum were prepared by collagenase digestion. The cells showed an all-or-none response to acetylcholine (ACh) under our experimental conditions. 2 Desensitized cells showed an all-or-none response but required a higher concentration of ACh for induction of contraction, indicating that the desensitization was due to a change in the threshold concentration. 4 The ACh-stimulated increase of the 45Ca2 + influx was very rapid and correlated well with the contraction of the cells. The concentrations of ACh inducing the maximal 45Ca2 + influx were increased by desensitization. 5 These results indicated that although the binding of ACh to the receptor was not changed by desensitization, the threshold concentration of ACh for their contraction was raised by desensitization, and the 45Ca2 + influx accompanying the contraction was shifted to the side of high concentration of ACh.6 These results suggest that the development of short-term desensitization is due to an uncoupling of the receptor from the mechanism for initiation of the contraction.

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“…Muscarinic receptor desensitization has previously been correlated with phosphorylation of the receptor in the chick and porcine heart, as well as in the brain (Ho, Ling, Dufield, Lam & Wang, 1987;Kwatra, Leung, Maan, McMahon, Ptasienski, Green & Hosey, 1987;Kwatra. Ptasienski & Hosey, 1989).…”

Section: Introductionmentioning

confidence: 97%

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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Phosphorylation of brain muscarinic receptor: Evidence of receptor regulation

Cited by 22 publications

References 11 publications

Novel regulation of muscarinic receptors and their coupling with G proteins in smooth muscle: transient resensitization during desensitizing process

Novel regulation of muscarinic receptors and their coupling with G proteins in smooth muscle: transient resensitization during desensitizing process

The change in the threshold for short‐term desensitization in isolated smooth muscle cells showing an all‐or‐none response to acetylcholine

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

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