Signal Transduction and Drug Action - The Merck Veterinary Manual

Signal Transduction and Drug Action

Most receptors are proteins. The best characterized of these are regulatory proteins, enzymes, transport proteins, and structural proteins. Nucleic acids are also important drug receptors, particularly for cancer chemotherapeutic agents.

The receptors for several neurotransmitters modulate ion channel opening and closing through ligand gating or voltage gating. The nicotinic acetylcholine receptor is an example of a ligand-gated receptor, which allows Na⁺ to flow down its concentration gradient into cells, resulting in depolarization. Most of the clinically useful neuromuscular blocking drugs used by anesthetists compete with acetylcholine for the receptor but do not initiate ion-channel opening. Other ligand-gated ion channels include the receptors for the excitatory amino acids (glutamate and aspartate), the inhibitory amino acids (γ-amino butyric acid [GABA] and glycine), and certain serotonin (5-HT₃) receptors. The sodium channel receptor is an example of a voltage-gated receptor; these are present in the membranes of excitable nerve, cardiac, and skeletal muscle cells. In the resting state, the Na⁺/K⁺ -ATPase pump in these cells maintains an intracellular Na⁺ concentration much lower than that in the extracellular environment. Membrane depolarization causes channel opening and a transient influx of Na⁺ ions, followed by inactivation and return to the resting state. The action of local anesthetics is due to their direct interaction with voltage-gated Na⁺ channels.

Many transmembrane receptors are linked to guanosine triphosphate binding proteins, which activate second messenger systems. Two important second messenger systems are cyclic adenosine monophosphate (cAMP) and the phosphoinositides. In cAMP second messenger systems, binding of the ligand to the receptor increases or decreases adenylyl cyclase activity, which in turn regulates the formation of cAMP from adenosine triphosphate. The activation of protein kinase A by cAMP results in the phosphorylation of proteins and a physiologic effect. From a therapeutic standpoint, drug binding to β-adrenergic, histamine H₂, or dopamine D₁ receptors activates adenylyl cyclase, whereas binding to muscarinic M₂, a₂ -adrenergic, dopamine D₂, opiate m and d, adenosine A₁, or GABA type B receptors inhibits adenylyl cyclase. In phosphoinositide second messenger systems, membrane phosphatidylinositol 4,5-biphosphate is hydrolyzed to 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG) by activation of a phospholipase C. Both IP3 and DAG activate kinases, and in the case of IP3, this involves the mobilization of calcium from intracellular stores. The action of numerous drugs is due to their interaction with receptors that rely on these second messengers, which include a₁-adrenergic, muscarinic M₁ or M₂, serotonin 5-HT₂, and thyrotropin-releasing hormone receptors.

Protein tyrosine kinase receptors are generally transmembrane enzymes that phosphorylate proteins exclusively on tyrosine residues, rather than on serine or threonine residues. They include endocrine hormone receptors for insulin and receptors for several growth hormones.

Intracellular receptors mediate the action of hormones such as glucocorticoids, estrogen, and thyroid hormone. These hormones, which regulate gene expression in the nucleus, are lipophilic and freely diffuse through the cell membrane to reach the receptor. Glucocorticoid receptors reside predominantly in the cytoplasm in an inactive form until they bind to the glucocorticoid steroid ligand. This results in receptor activation and translocation to the nucleus, where the receptor interacts with specific DNA sequences. Unlike glucocorticoid receptors, the receptors for estrogen and thyroid hormone reside in the nucleus.