Biochemical Effects Of Muscarinic Receptor Stimulation

Transmission at the synapse involving second messengers is much slower, about 100 ms, compared with the few milliseconds at synapses where ion channels are activated directly. The delayed reaction to receptor stimulation is caused by a cascade of biochemical events that must occur to cause the pharmacological response (Fig. 17.4). The sequence of events in these second-messenger systems begins with activation of the receptors by an agonist and involves the activation of G proteins that are bound to a portion of the intracellular domain of the muscarinic receptor.20 G proteins are so called because of their interaction with the guanine nucleotides GTP and guanosine diphosphate (GDP). They translate drug-receptor interactions at the surface of the cell to components inside the cell to create the biological response. G proteins consist of three subunits, a, 3, and y. When the receptor is occupied, the a subunit, which has enzymatic activity, catalyzes the conversion of GTP to GDP. The a subunit bound with GTP is the active form of the G protein that can associate with various enzymes (i.e., PLC and adenylate cyclase) and ion channels (K+ and Ca2+). G proteins are varied, and the a subunit may cause activation (Gs) or inactivation (Gi) of the enzymes or channels. Recent studies suggest that 3 and y subunits also contribute to pharmacological effects.21

A single drug-receptor complex can activate several G protein molecules, and each in turn can remain associated with a target molecule (e.g., an enzyme) and cause the production of many molecules, amplifying the result of the

ACh

Adenylate Cyclase System b

Figure 17.4 • Proposed biochemical mechanisms of cholinergic receptor action. A. ACh activates a G protein (a, p, y) in the phospholipase system to activate the membrane enzyme phospholipase C (PLC), enhancing muscle contraction. B. Inhibition of adenylate cyclase system through an inhibitory G protein (a1) to cause muscle relaxation.

Adenylate Cyclase System b

Figure 17.4 • Proposed biochemical mechanisms of cholinergic receptor action. A. ACh activates a G protein (a, p, y) in the phospholipase system to activate the membrane enzyme phospholipase C (PLC), enhancing muscle contraction. B. Inhibition of adenylate cyclase system through an inhibitory G protein (a1) to cause muscle relaxation.

initial drug-receptor combination. M1, M3, and M5 receptors activate PLC, causing the release of IP3 and DAG, which in turn release intracellular Ca2+ and activate protein kinases, respectively. M2 and M4 receptors produce inhibition of adenylate cyclase.

Phosphoinositol System. The phosphoinositol system requires the breakdown of membrane-bound phosphatidyli-nositol 4,5-diphosphate (PIP2) by PLC to IP3 and DAG, which serve as second messengers in the cell. IP3 mobilizes Ca2+ from intracellular stores in the endoplasmic reticulum to elevate cytosolic free Ca2+. The Ca2+ activates Ca2+-dependent kinases (e.g., troponin C in muscle) directly or binds to the Ca2+-binding protein calmodulin, which activates calmodulin-dependent kinases. These kinases phos-phorylate cell-specific enzymes to cause muscle contraction. DAG is lipidlike and acts in the plane of the membrane through activation of protein kinase C to cause the phosphorylation of cellular proteins, also leading to muscle contraction (Fig. 17.4).22,23

Adenylate Cyclase. Adenylate cyclase, a membrane enzyme, is another target of muscarinic receptor activation. The second-messenger cAMP is synthesized within the cell from adenosine triphosphate (ATP) by the action of adenyl-ate cyclase. The regulatory effects of cAMP are many, as it can activate various protein kinases. Protein kinases catalyze the phosphorylation of enzymes and ion channels, altering the amount of calcium entering the cell and thus affecting muscle contraction. Muscarinic receptor activation causes lower levels of cAMP, reducing cAMP protein-dependent kinase activity, and a relaxation of muscle contraction. Some have suggested that a GTP-inhibitory protein (Gi) reduces the activity of adenylate cyclase, causing smooth muscle relaxation (Fig. 17.4).20,24

Ion Channels. In addition to the action of protein ki-nases that phosphorylate ion channels and modify ion conductance, G proteins are coupled directly to ion channels to regulate their action.24 The Ca2+ channel on the cell membrane is activated by G proteins without the need of a second messenger to allow Ca2+ to enter the cell. The a subunit of the G protein in heart tissue acts directly to open the K+ channel, producing hyperpolarization of the membrane and slowing the heart rate.

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