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major receptor family

Pharmacology defines a receptor as any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors. However, the richest sources of therapeutically exploitable pharmacologic receptors are proteins that are responsible for transducing extracellular signals into intracellular responses. These receptors may be divided into four families: 

1) ligand-gated ion channels, 
2) G proteincoupled receptors,
3) enzyme-linked receptors, and
4) intracellular receptors


Figure 2.2 Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of a serpentine receptor, which is coupled to a G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.


The type of receptor a ligand will interact with depends on the nature of the ligand. Hydrophobic ligands interact with receptors that are found on the cell surface (families 1, 2, and 3). In contrast, hydrophobic ligands can enter cells through the lipid bilayers of the cell membrane to interact with receptors found inside cells (family 4)


A. Ligand-gated ion channels

The first receptor family comprises ligand-gated ion channels that are responsible for regulation of the flow of ions across cell membranes (see Figure above A).

The activity of these channels is regulated by the binding of a ligand to the channel. Response to these receptors is very rapid, having durations of a few milliseconds. The nicotinic receptor and the γaminobutyric acid (GABA) receptor are important examples of ligand-gated receptors, the functions of which are modified by numerous drugs. Stimulation of the nicotinic receptor by acetylcholine results in sodium influx, generation of an action potential, and activation of contraction in skeletal muscle. Benzodiazepines, on the other hand, enhance the stimulation of the GABA receptor by GABA, resulting in increased chloride influx and hyperpolarization of the respective cell. Although not ligand-gated, ion channels, such as the voltage-gated sodium channel, are important drug receptors for several drug classes, including local anesthetics. 


B. G protein–coupled receptors

A second family of receptors consists of G protein–coupled receptors. These receptors are comprised of a single peptide that has seven membrane-spanning regions, and these receptors are linked to a G protein (Gs and others) having three subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit.


Figure : The recognition of chemical signals by G protein-coupled membrane receptors triggers an increase (or, less often, a decrease) in the activity of adenylyl cyclase.


 Binding of the appropriate ligand to the extracellular region of the receptor activates the G protein so that GTP replaces guanosine diphosphate (GDP) on the α subunit. Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit subsequently interact with other cellular effectors, usually an enzyme or ion channel. These effectors then change the concentrations of second messengers that are responsible for further actions within the cell. Stimulation of these receptors results in responses that last several seconds to minutes. 

-Second messengers: These are essential in conducting and amplifying signals coming from G protein–coupled receptors. A common pathway turned on by Gs, and other types of G proteins, is the activation of adenylyl cyclase by α-GTP subunits, which results in the production of cyclic adenosine monophosphate (cAMP)—a second messenger that regulates protein phosphorylation. G proteins also activate phospholipase C, which is responsible for the generation of two other second messengers, namely inositol-1,4,5-trisphosphate and diacylglycerol. These effectors are responsible for the regulation of intracellular free calcium concentrations, and of other proteins as well. This family of receptors transduces signals derived from odors, light, and numerous neurotransmitters, including norepinephrine, dopa-mine, serotonin, and acetylcholine. G protein–coupled receptors also activate guanylyl cyclase, which converts (GTP) to cyclic guanosine monophosphate (cGMP), a fourth second messenger that stimulates cGMP-dependent protein kinase. cGMP signaling is important in only a few cells, for example, intestinal mucosa and vascular smooth muscle, where it causes relaxation of vascular smooth muscle cells. Some drugs such as sildenafil produce vasodilation by interfering with specific phosphodiesterases, the enzymes that metabolically break down cGMP. 



C. Enzyme-linked receptors

A third major family of receptors consists of those having cytosolic enzyme activity as an integral component of their structure or function (see Figure  above C).

Binding of a ligand to an extracellular domain activates or inhibits this cytosolic enzyme activity. Duration of responses to stimulation of these receptors is on the order of minutes to hours. The most common enzyme-linked receptors (epidermal growth factor, platelet-derived growth factor, atrial natriuretic peptide, insulin, and others) are those that have a tyrosine kinase activity as part of their structure. Typically, upon binding of the ligand to receptor subunits, the receptor undergoes conformational changes, converting from its inactive form to an active kinase form. The activated receptor autophosphorylates, and phosphorylates tyrosine residues on specific proteins. The addition of a phosphate group can substantially modify the three-dimensional structure of the target protein, thereby acting as a molecular switch. For example, when the peptide hormone insulin binds to two of its receptor subunits, their intrinsic tyrosine kinase activity causes autophosphorylation of the receptor itself. In turn, the phosphorylated receptor phosphorylates target molecules—insulin-receptor substrate peptides—that subsequently activate other important cellular signals such as IP3 and the mitogen-activated protein kinase system. This cascade of activations results in a multiplication of the initial signal, much like that which occurs with G protein–coupled receptors



D. Intracellular receptors

The fourth family of receptors differs considerably from the other three in that the receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell to interact with the receptor 


Figure  Mechanism of intracellular receptors.


This places constraints on the physical and chemical properties of the ligand in that it must have sufficient lipid solubility to be able to move across the target cell membrane. Because these receptor ligands are lipid soluble, they are transported in the body attached to plasma proteins, such as albumin. For example, steroid hormones exert their action on target cells via this receptor mechanism. Binding of the ligand with its receptor follows a general pattern in which the receptor becomes activated because of the dissociation of a small repressor peptide. The activated ligand–receptor complex migrates to the nucleus, where it binds to specific DNA sequences, resulting in the regulation of gene expression.

 The time course of activation and response of these receptors is much longer than that of the other mechanisms described above. Because gene expression and, therefore, protein synthesis is modified, cellular responses are not observed until considerable time has elapsed (thirty minutes or more), and the duration of the response (hours to days) is much greater than that of other receptor families.



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