Question

Explain why the M2 subtype of muscarinic ACh receptors is found on the autorhythmic cells of the sinoatrial node and the M3 subtype is found on smooth muscle fibers of the bronchioles.

Answer 1

1.Explanation :The parasympathetic component of the autonomic nervous system plays an important role in the physiological regulation of cardiac function by exerting significant influence over the initiation as well as propagation of electrical impulses, in addition to being able to regulate contractile force. These effects are mediated in whole or in part through changes in ion channel activity that occur in response to activation of M2 muscarinic cholinergic receptors following release of the neurotransmitter acetylcholine. The coupling of M2 receptor activation to most changes in cardiac ion channel function can be explained by one of two general paradigms. The first involves direct G protein-dependent regulation of ion channel activity. The second involves indirect regulation of ion channel activity through modulation of cAMP-dependent responses. This review focuses on recent advances in our understanding of the mechanisms by which M2 muscarinic receptor activation both inhibits and facilitates cAMP-dependent ion channel responses in the heart.

2.Explanation-The M₃ muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands, lungs, pancreas and the brain. In the CNS, they induce emesis. Muscarinic M₃ receptors are expressed in regions of the brain that regulate insulin homeostasis, such as the hypothalamus and dorsal vagal complex of the brainstem. These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion.In general, they cause smooth muscle contraction and increased glandular secretions.

Because the M₃ receptor is G_q-coupled and mediates an increase in intracellular calcium, it typically causes constriction of smooth muscle, such as that observed during bronchoconstriction. However, with respect to vasculature, activation of M₃ on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and vasodilation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M₃ mediates vasoconstriction in pathologies wherein the vascular endothelium is disrupted.