Muscarinic Receptor Subtypes

Evidence from both pharmacological and biochemical studies shows that subtypes of muscarinic receptors are located in the CNS and peripheral nervous system.13,14 Molecular cloning studies have revealed the existence of five different molecular mammalian muscarinic receptor proteins. The cloned receptors have been identified as m1 to m5. In another

Figure 17.3 • Hypothetical model of a muscarinic receptor showing the location of the transmembrane helical protein domains and the extracellular and intracellular domains connecting the seven a-helical proteins in the membrane. (Reprinted from Goyal, R. K.: N. Engl. J. Med. 321:1024, 1989, with permission from the author and the Massachusetts Medical Society.)

Figure 17.3 • Hypothetical model of a muscarinic receptor showing the location of the transmembrane helical protein domains and the extracellular and intracellular domains connecting the seven a-helical proteins in the membrane. (Reprinted from Goyal, R. K.: N. Engl. J. Med. 321:1024, 1989, with permission from the author and the Massachusetts Medical Society.)

method of identification, muscarinic receptor subtypes have been defined on the basis of their affinity for selective agonists and antagonists and the pharmacological effects they cause. These receptors are designated with capital letters and subscript numbers as M1 to M5. The nomenclature convention adopted for these receptors is that the pharmacologically defined subtypes M1, M2, and M3 correspond to the genetically defined subtypes m1, m2, and m3. The m4 gene-derived protein is referred to as the M4 subtype and has many pharmacological properties similar to those of the M2 subtype. The m5 receptor gene product does not have an equivalent pharmacological profile.

M1 Receptors. Even though molecules do not have exclusive selectivity on muscarinic receptor subtypes, M1 receptors have been defined as those with high affinity for pirenzepine and low affinity for compounds such as AF-DX 116. They have been termed neural because of their distribution within particular brain structures. In addition to the CNS, M1 receptors are located in exocrine glands and auto-nomic ganglia. In humans, these receptors seem to affect arousal attention, rapid eye movement (REM) sleep, emotional responses, affective disorders including depression, and modulation of stress. They are believed to participate in higher brain functions, such as memory and learning. Alzheimer disease research has implicated cholinergic neurons and receptors, but evidence does not show conclusively that these are the primary causes of the disease. M1 receptors have been identified in submucosal glands and some smooth muscle. They are located in parietal cells in the gastrointestinal (GI) tract and in peripheral autonomic ganglia, such as the intramural ganglia of the stomach wall. When stimulated, M1 receptors cause gastric secretion.15 Although McN-A343 is a selective agonist, pirenzepine hydrochloride (HCl) acts as an antagonist and has been used outside the United States for the treatment of peptic ulcer disease.

M2 Receptors. M2 receptors are identified by their high affinity for methoctramine, a polyamine, and by their low affinity for pirenzepine. M2 receptors are also called cardiac muscarinic receptors because they are located in the atria and conducting tissue of the heart. Their stimulation causes a decrease in the strength and rate of cardiac muscle contraction. These effects may be produced by affecting intracellular K+ and Ca2+ levels in heart tissue. M2 receptors activate K+ channels to cause hyperpolarization of cardiac cells, resulting in bradycardia. These receptors may also act through an inhibitory G protein (Gi) to reduce adenylate cyclase activity and lower cyclic 3',5'-adenosine monophosphate (cAMP) levels in cardiac cells. Lower cAMP levels decrease the amount of free Ca2+ in cardiac cells and slow down the heart rate.16 M2 receptors can also serve as autore-ceptors on presynaptic terminals of postganglionic cholinergic nerves to inhibit ACh release. The balance of the effects of multiple muscarinic receptor subtypes determines the size of the airway of the smooth muscle in the bronchioles. Contraction is primarily the result of the action of ACh on M3 receptors (see on next page) following stimulation of the vagus. At the same time, ACh stimulates inhibitor M2 au-toreceptors located on nerve endings to limit release of ACh. In asthmatics, neuronal M2 receptors in the lungs do not function normally.17

M3 Receptors. M3 receptors, referred to as glandular muscarinic receptors, are located in exocrine glands and smooth muscle. Their effect on these organ systems is mostly stimulatory. Glandular secretions from lacrimal, salivary, bronchial, pancreatic, and mucosal cells in the GI tract are characteristic of M3 receptor activation. Contraction of visceral smooth muscle is also a result of M3 receptor stimulation. These stimulant effects are mediated through G protein activation of phospholipase C (PLC) to form the second-messenger inositol triphosphate (IP3) and diacylglycerol (DAG). Discoveries in the past decade have revealed that the endothelium can control the tone of vascular smooth muscle by the synthesis of a potent relaxant, endothelium-derived relaxing factor (EDRF), now identified as nitric oxide (NO), and a vasoconstrictor substance, endothelium-derived contracting factor (EDCF). The synthesis and release of these substances contribute to the tone of the vascular epithelium. M3 receptors, when activated in endothelial cells, cause the release of EDRF and contribute to vasodilation.18

M4 Receptors. M4 receptors, like M2 receptors, act through Gi protein to inhibit adenylate cyclase. They also function by a direct regulatory action on K+ and Ca2+ ion channels. M4 receptors in tracheal smooth muscle, when stimulated, inhibit the release of ACh19 in the same manner that M2 receptors do.

M5 Receptors. A great deal of research remains to be performed on the M5 subclass of receptors. Because the M5 receptor messenger RNA (mRNA) is found in the substan-tia nigra, it has been suggested that M5 receptors may regulate dopamine release at terminals within the striatum.

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