Activation of M3 muscarinic acetylcholine receptors inhibits voltage-dependent calcium influx in small cell lung carcinoma

Carol L. Williams, Vanda A Lennon

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Small cell carcinoma of the lung (SCC) expresses several characteristics of neuronal cells, including voltage-gated Ca2+ channels (VGCC), and also expresses muscarinic acetylcholine receptors (mAChR). In testing the possibility that VGCC may be functionally coupled to mAChR in SCC cell lines, we found that depolarization-dependent Ca2+ influx was inhibited by carbachol (IC50 = 0.78 μM) and oxotremorine (IC50 = 0.69 μM). Equilibrium dissociation constants for several mAChR antagonists indicated that a mAChR of M3 subtype was involved. Exposure of SCC to carbachol induced the hydrolysis of phosphoinositides and increased the cytosolic free Ca2+ concentration ([Ca2+]i). The carbachol-mediated inhibition of depolarizationdependent Ca2+ influx did not directly correlate with increased [Ca2+]i but did correlate with inositol polyphosphate generation. The protein kinase C activators phorbol 12-myristate 13-acetate or 1-oleoyl-2-acetylsn-glycerol neither mimicked nor amplified the inhibitory effect of carbachol on Ca2+ influx. However, phorbol 12-myristate 13-acetate suppressed the carbachol-induced inositol polyphosphate generation and inhibition of depolarization-dependent Ca2+ influx. The inactive compound 4α-phorbol had no effect. These data suggest that the inhibition of VGCC caused by carbachol is not due to protein kinase C activation, but rather is due to events mediated by inositol polyphosphates. This is the first documentation of a role for phosphoinositide hydrolysis in the functional coupling of mAChR and VGCC. The expression of M3 mAChR functionally coupled to VGCC could have therapeutic implications for SCC, in light of recent demonstrations that cell proliferation can be influenced by activation of neurotransmitter receptors.

Original languageEnglish (US)
Pages (from-to)1443-1447
Number of pages5
JournalJournal of Biological Chemistry
Volume265
Issue number3
StatePublished - Jan 25 1990

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Small Cell Lung Carcinoma
Carbachol
Muscarinic Receptors
Chemical activation
Cells
Calcium
Polyphosphates
Electric potential
Inositol
Depolarization
Phosphatidylinositols
Protein Kinase C
Inhibitory Concentration 50
Hydrolysis
Acetates
Muscarinic M3 Receptors
Neurotransmitter Receptor
Cell proliferation
Cholinergic Antagonists
Documentation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Activation of M3 muscarinic acetylcholine receptors inhibits voltage-dependent calcium influx in small cell lung carcinoma. / Williams, Carol L.; Lennon, Vanda A.

In: Journal of Biological Chemistry, Vol. 265, No. 3, 25.01.1990, p. 1443-1447.

Research output: Contribution to journalArticle

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