Inhibition of the L-type calcium channel by the five muscarinic receptors (m1-m5) expressed in NIH 3T3 cells

Pemberton, Kyle; Jones, S. V. P.

doi:10.1007/s004240050306

Cited by 23 publications

(25 citation statements)

References 50 publications

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“…In this respect, our present results have provided the intriguing possibility that a muscarinic receptor pharmacologically indistinguishable from the M5 receptor upregulates L-type Ca 2+ channel activities via activation of a specific PKC pathway and may contribute to enhancing the gastric motility (see below). Recently, modulation of Ltype Ca 2+ channels by muscarnic receptors was investigated by recombinantly expressing five subtypes of muscarinic receptors (m1 -m5) into an established fibroblast cell line, NIH 3T3 cells (28). Somewhat unexpectedly, stimulation of PI turnover-linked receptors, i.e., m1, m3 and m5 receptors by ACh all resulted in inhibition of Ca 2+ currents via activation of PKC, thus seemingly contradicting the results of the present study.…”

Section: +contrasting

confidence: 96%

Possible Involvement of M5 Muscarinic Receptor in the Enhancing Actions of the Novel Gastroprokinetic Agent Z-338 on Nifedipine-Sensitive Voltage-Dependent Ca2+ Currents in Guinea Pig Stomach

Morita

Abe

Ito

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the effects of the novel gastroprokinetic agent Z-338 (N-(N'-N'-diisopropylaminoethyl)-[2-(2-hydroxy-4,5-dimethoxybenzoylamino)-1,3-thiazole-4-yl] carboxyamide monohydrochloride trihydrate) on L-type voltage-dependent Ca 2+ currents (ICa) in guinea pig gastric myocytes by using the whole-cell patch clamp technique. Bath-applied acetylcholine (ACh) produced biphasic effects on ICa, i.e., enhancement (1 -100 nM) and inhibition (1 -100 mM), both of which were abolished by pretreatment with atropine (10 mM) or intracellular perfusion of GDPbS (500 mM). Z-338 (³1 nM, ED50: 120 nM) mimicked the enhancing effects of ACh, but did not inhibit ICa. The effects of Z-338 and ACh were non-additive and blocked by atropine and GDPb S, but not by pertussis toxin (PTX) pretreatment (500 ng /ml). ACh (³1 m M) induced slow inward currents via activation of the muscarinic receptor /PTX-sensitive G-protein pathway, but Z-338 was devoid of these effects. Neither pirenzepine (1 m M), AF-DX116 (1 mM), nor oxybutynin (100 nM) could prevent Z-338 (1 mM) and ACh (10 nM) from enhancing I Ca , whilst 4-DAMP (100 nM) blocked the effects of Z-338 and ACh. Bath-application of protein kinase C (PKC) activator PDBu (phorbol-12,13-dibutyrate) (250 nM) enhanced I Ca , and conversely, pipette inclusion of PKC inhibitor peptide (150 mM) abolished the effects of ACh and Z-338 on I Ca . These results collectively suggest that although contribution of the M 3 receptor is not excluded, the major actions of Z-338 on gastric myocytes are potentiation of I Ca through activation of M 5 -like receptor.Keywords: Z-338, M5 muscarinic receptor, L-type calcium channel, Gastric smooth muscle Z-338, a novel carboxyamide derivative, has recently been synthesized, in the hope to obtain more potent and clinically safer gastroprokinetic agents having a different mechanism from those of existing gastroprokinetic agents such as cisapride and domperidone, which have been reported to show unfavorable adverse effects on the central nervous and cardiovascular systems (1). It has been shown that Z-338 enhances gastric motor activity in conscious dogs with chronically implanted force transducers and restores gastric emptying suppressed by clonidine treatment in both dog and rat gastroparesis models (1). The mechanisms involved in theses actions of Z-338 have been investigated in more detail by a number of different techniques. In guinea pig stomach strips preincubated with [3 H]-labelled choline, Z-338 enhances the electrically stimulated release of [ 3 H]-ACh. This is likely to occur through inhibition of M1 and M2 receptors, since Z-338 can bind to M1 and M2 (but not M3) receptors prepared from rat tissues and effectively block membrane currents associated with activation of recombinantly expressed rat M1 and M2 receptors in Xenopus oocytes (2). Furthermore, it was also found that Z-338 enhances spontaneous contractions as well as electrically evoked excitatory junction potentials and concomitant contractions in guinea pig stomach with no significan...

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Section: +contrasting

confidence: 96%

Possible Involvement of M5 Muscarinic Receptor in the Enhancing Actions of the Novel Gastroprokinetic Agent Z-338 on Nifedipine-Sensitive Voltage-Dependent Ca2+ Currents in Guinea Pig Stomach

Morita

Abe

Ito

et al. 2002

Japanese Journal of Pharmacology

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“…L-type channels appear to be a consistent target for the inhibitory action of protein kinase C activators in several Ž cell types Haymes et al, 1992;Bouron et al, 1995; . Pemberton and Jones, 1997;Zhang et al, 1997 . Consistent with the results described in this study, we have previously reported that PMA inhibits high K q -evoked Ž catecholamine release from bovine chromaffin cells 23-. Ž .…”

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confidence: 81%

“…Ž 1993 or inhibition Rane et al, 1989;Chik et al, 1996; . Pemberton and Jones, 1997;Redman et al, 1997 of depolarization-evoked Ca 2q currents, depending on the cell type. In chromaffin cells, protein kinase C activation Ž either has no effect Burgoyne and Norman, 1984;Morita .…”

Section: Introductionmentioning

confidence: 99%

Regulation of Ca2+ influx by a protein kinase C activator in chromaffin cells: differential role of P/Q- and L-type Ca2+ channels

Sena

Santos

Boarder

et al. 1999

European Journal of Pharmacology

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Phorbol esters reduce depolarization-evoked Ca 2q influx in adrenal chromaffin cells, suggesting that voltage-sensitive Ca 2q channels Ž . VSCCs are inhibited by protein kinase C-mediated phosphorylation. We now address the possibility that L-and PrQ-type Ca channel Ž . subtypes might be differentially involved in phorbol ester action. In bovine chromaffin cells, short-term 10 min incubations with phorbol Ž .Žw 2q x . 12-myristate 13-acetate PMA inhibited early high K -evoked rises in cytosolic free Ca concentration Ca and the early i 2q

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“…Several studies support a role for PKC in the enhancement (Swartz, 1993;Yang and Tsien, 1993;Kamatchi et al, 2003) or inhibition (Pemberton and Jones, 1997;Rane and Dunlap, 1986) of depolarization-evoked Ca v currents by DAG, PMA or MCh. Although the auxiliary β subunit is required for this action (Stea et al, 1995;Kamatchi et al, 2003) most evidence suggests that PKC targets the α 1 subunit.…”

Section: Discussionmentioning

confidence: 94%

Protein kinase C isozyme-specific potentiation of expressed Cav 2.3 currents by acetyl-β-methylcholine and phorbol-12-myristate, 13-acetate

et al. 2008

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Protein kinase C (PKC) is implicated in the potentiation of Ca v 2.3 currents by acetyl-β-methylcholine (MCh), a muscarinic M 1 receptor agonist or phorbol-12-myristate, 13-acetate (PMA). The PKC isozymes responsible for the action of MCh and PMA were investigated using translocation as a measure of activation and with isozyme-selective antagonists and siRNA. Ca v channels were expressed with α 1 2.3, β 1 b and α 2 δ subunits and muscarinic M 1 receptors in the Xenopus oocytes and the expressed currents (I Ba ) were studied using Ba 2+ as the charge carrier. Translocation of PKC isozymes to the membrane studied by Western blot revealed that all eleven known PKC isozymes are present in the Xenopus oocytes. Exposure of the oocytes to MCh led to the translocation of PKC α whereas PMA activated PKC βII and ε isozymes. The action of MCh was inhibited by Go 6976, an inhibitor of cPKC isozymes or PKC α siRNA. PMA-induced potentiation of Ca v 2.3 currents was inhibited by CG533 53, a PKC βII antagonist, βIIV5.3, a peptide translocation inhibitor of PKC βII or PKC βII siRNA. Similarly, εV1.2, a peptide translocation inhibitor of PKC ε or PKC ε siRNA inhibited PMA action. The inhibitors of PKC increased the basal I Ba slightly. It is possible that some PKC isozymes have negative control over the I Ba . Our results implicate PKC α in the potentiation of Ca v 2.3 currents by MCh and PKC βII and ε in the potentiation of Ca v 2.3 currents by PMA. Classification of termsSection: 3. Neurophysiology, Neruopharmacology and other forms of Interceullular communication

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Inhibition of the L-type calcium channel by the five muscarinic receptors (m1-m5) expressed in NIH 3T3 cells

Cited by 23 publications

References 50 publications

Possible Involvement of M5 Muscarinic Receptor in the Enhancing Actions of the Novel Gastroprokinetic Agent Z-338 on Nifedipine-Sensitive Voltage-Dependent Ca2+ Currents in Guinea Pig Stomach

Possible Involvement of M5 Muscarinic Receptor in the Enhancing Actions of the Novel Gastroprokinetic Agent Z-338 on Nifedipine-Sensitive Voltage-Dependent Ca2+ Currents in Guinea Pig Stomach

Regulation of Ca2+ influx by a protein kinase C activator in chromaffin cells: differential role of P/Q- and L-type Ca2+ channels

Protein kinase C isozyme-specific potentiation of expressed Cav 2.3 currents by acetyl-β-methylcholine and phorbol-12-myristate, 13-acetate

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