Chapter 6 Pharmacological aspects of the inositide response in the central nervous system: the muscarinic acetylcholine receptor

Abstract

Publisher Summary Receptor-sensitive operation of the inositide cycle constitutes a second messenger system with rapidly growing experimental support and physiological implications. Inositide turnover is involved in the release of free fatty acids (mainly arachidonate), intracellular mobilization of Ca 2+ , and the activation of protein kinase C. Several neurotransmitter receptors have been investigated in the central nervous system in regard to their linkage to the inositide cycle. For most neurotransmitters, different receptor types or subtypes can be identified pharmacologically. The inositide-response to acetylcholine (Ach) is mediated through the muscarinic and not the nicotinic receptor type. Of all neurotransmitter receptors, the muscarinic ACh receptor (mAChR) has been most intensively studied for its coupling to the inositide cycle. This chapter presents a study in which the affinities of various mAChR ligands to the M 1 - and M 2 AChR are compared with their potency to either evoke or inhibit an inositide response in the rat forebrain neuronal process endings (NPE). The potencies of mAChR antagonist to inhibit the inositide response to carbamylcholine (CCh) corresponded best with ligand affinities for the M 1 AChR. The potencies of mAChR agonists to evoke an inositide response corresponded best with ligand affinities for the M 2 AChR. The latter is further supported by the fact that N -ethylmaleimide (NEM), which specifically lowers the affinity of the M 2 AChR, enhances the inositide effect to CCh.