Pemberton K E, Jones S V
Department of Psychiatry and Molecular Physiology, University of Vermont College of Medicine, Burlington 05405, USA.
Pflugers Arch. 1995 Mar;429(5):699-707. doi: 10.1007/BF00373991.
Activation of muscarinic receptors has been shown to inhibit L-type calcium conductances by mechanisms sensitive to pertussis toxin (PTX). In this study we show that agonist stimulation of the m4 muscarinic receptor leads to an increase in an L-type calcium conductance in the AtT-20 pituitary cell line, by a PTX-sensitive mechanism. The amplitude of the dihydropyridine (DHP)-sensitive or L-type calcium current was increased by acetylcholine (ACh), with no shift in the voltage dependence. This action of ACh was completely inhibited by PTX pre-treatment. Forskolin, cAMP and phorbol 12,13-dibutyrate reduced, while RpcAMPs, an inhibitor of cAMP-dependent protein kinase (PKA), increased the L-type calcium conductance. We propose that the m4 muscarinic receptor activates the L-type calcium channel by inhibition of adenylyl cyclase resulting in reduced cAMP levels and, hence, reduced PKA activity. This novel increase in calcium current via the m4 muscarinic receptor appears to reflect the coupling with an L-type channel of the D class, due to the sensitivity of the L-type calcium conductance to both DHPs and omega-conotoxin, and, thus, is distinct from the skeletal muscle and cardiac L-type channels of the C class previously studied.
毒蕈碱受体的激活已被证明可通过对百日咳毒素（PTX）敏感的机制抑制L型钙电导。在本研究中，我们表明，毒蕈碱受体m4的激动剂刺激通过一种对PTX敏感的机制，导致AtT-20垂体细胞系中L型钙电导增加。二氢吡啶（DHP）敏感的或L型钙电流的幅度因乙酰胆碱（ACh）而增加，电压依赖性无变化。ACh的这一作用被PTX预处理完全抑制。福斯高林、cAMP和佛波醇12,13 - 二丁酸酯使其降低，而cAMP依赖性蛋白激酶（PKA）的抑制剂RpcAMPs则增加L型钙电导。我们提出，毒蕈碱受体m4通过抑制腺苷酸环化酶激活L型钙通道，导致cAMP水平降低，从而使PKA活性降低。经由毒蕈碱受体m4的这种新型钙电流增加似乎反映了与D类L型通道的偶联，因为L型钙电导对DHP和ω-芋螺毒素均敏感，因此，与先前研究的C类骨骼肌和心脏L型通道不同。
