There are two major distinct classes of cholinergic receptors, the muscarinic and nicotinic receptors. Five muscarinic receptors (M1 through M5) have been cloned (Kandel et al. 2000). These receptors are G protein-coupled and act either by regulating ion channels (in particular, K+ or Ca2+) or through being linked to second-messenger systems. Generally speaking, M1, M3, and M5 are coupled to phosphoinositol hydrolysis, whereas M2 and M4 are coupled to inhibition of adenylyl cyclase and regulation of K+ and Ca2+ channels (Cooper et al. 2001) (see Figure 1-6B).
By contrast, the nicotinic receptors are ionotropic receptors, and at least seven different functional receptors (based on different subunit composition) have been identified. Biochemical and biophysical data indicate that the nicotinic receptors in the muscle are formed from five protein subunits, with the stoichiometry of (Kandel et al. 2000). The binding of ACh molecules on the ct subunit is necessary for channel activation. By contrast, neuronal nicotinic receptors contain only two types of subunits (ctand 3), with the a occurring in at least seven different forms and the [3 in three (Cooper et al. 2001). Nicotinic receptors may be the targets of considerable cross-talk, as a variety of kinases (including PKA, PKC, and tyrosine kinases) are able to regulate the sensitivity of this receptor. A number of regulatory mechanisms exist. For example, the mammalian prototoxin lynx1 acts as an allosteric modulator of nicotinic acetylcholine receptors (Miwa et al. 2006).
From a clinical standpoint, Freedman et al. (1997) demonstrated that in a cohort of patients with schizophrenia, abnormal P50 auditory evoked potentials were linked to a susceptibility locus for this disease on chromosome 15. Notably, this is where a nicotinic receptor subunit is found, providing indirect support for the long-standing contention that the high rates of cigarette smoking in patients with schizophrenia may represent (at least in part) an attempt to correct an underlying nicotinic receptor defect.
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