Physiological Receptors Structural And Functional Families

Receptors for physiological regulatory molecules can be assigned to a relatively few functional families whose members share both common mechanisms of action and similar molecular structures (Figure 1-7). For each receptor superfamily, there is now a context for understanding the structures of ligand-binding domains and effector domains and how agonist binding influences the regulatory activity of the receptor. The relatively small number of biochemical mechanisms and structural formats used for cellular signaling is fundamental to the ways in which target cells integrate signals from multiple receptors to produce additive, sequential, synergistic, or mutually inhibitory responses.

Receptors as Enzymes: Receptor Protein Kinases and Guanylyl Cyclases

A large group of receptors with intrinsic enzymatic activity consists of cell surface protein kinases, which exert their regulatory effects by phosphorylating diverse effector proteins at the inner face of the plasma membrane. Protein phosphorylation is a common mechanism for altering the biochemical activities of an effector or its interactions with other proteins. Most receptors that are protein kinases phosphorylate tyrosine residues in their substrates. A few receptor protein kinases phosphorylate serine or threonine residues. The most structurally simple receptor protein kinases are composed of an agonist-binding domain on the extracellular surface of the plasma membrane, a single membrane-spanning element, and a protein kinase domain on the inner membrane face. Many variations on this basic architecture exist, including assembly of multiple subunits in the mature receptor, obligate oligomerization of the liganded receptor, and the addition of multiple regulatory or protein-binding domains to the intracellular protein kinase domain that permit association of the liganded receptor with additional effector molecules and with substrates.

Another family of receptors, protein kinase—associated receptors, lack the intracellular enzymatic domains but, in response to agonists, bind or activate distinct protein kinases on the cyto-plasmic face of the plasma membrane.

For the receptors that bind atrial natriuretic peptides and the peptides guanylin and uroguanylin, the intracellular domain is not a protein kinase but rather a guanylyl cyclase that synthesizes the second messenger cyclic guanosine monophosphate (cyclic GMP), which activates a cyclic GMP-dependent protein kinase (PKG) and can modulate the activities of several cyclic nucleotide phosphodiesterases, among other effectors.

Protease-Activated Receptor Signaling

Proteases that are anchored to the plasma membrane or that are soluble in the extracellular fluid (e.g., thrombin) can cleave ligands or receptors at the surface of cells to either initiate or terminate signal transduction. Peptide agonists often are processed by proteolysis to become active at their receptors. Targeting the proteolytic regulation of receptor mechanisms has produced successful therapeutic strategies, such as the use of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension (see Chapters 30 and 32) and the generation of new anticoagulants targeting the action of thrombin (see Chapter 54).

Ion Channels

Receptors for several neurotransmitters form agonist-regulated ion-selective channels in the plasma membrane, termed ligand-gated ion channels or receptor operated channels, that convey their signals by altering the cell's membrane potential or ionic composition. This group includes the nicotinic cholinergic receptor, the y-aminobutyric acid A (GABAa) receptor, and receptors for glutamate, aspartate, and glycine (see Chapters 9, 12, and 16). They are all multisubunitproteins, with each subunit predicted to span the plasma membrane several times. Symmetrical association of the subunits allows each to form a segment of the channel wall, or pore, and to cooperatively

FIGURE 1-7 Structural motifs of physiological receptors and their relationships to signaling pathways. Schematic diagram of the diversity of mechanisms for control of cell function by receptors for endogenous agents acting via the cell surface or at calcium storage sites or in the nucleus. Detailed descriptions of these signaling pathway are given throughout the text in relation to the therapeutic actions of drugs affecting these pathways.

FIGURE 1-7 Structural motifs of physiological receptors and their relationships to signaling pathways. Schematic diagram of the diversity of mechanisms for control of cell function by receptors for endogenous agents acting via the cell surface or at calcium storage sites or in the nucleus. Detailed descriptions of these signaling pathway are given throughout the text in relation to the therapeutic actions of drugs affecting these pathways.

control channel opening and closing. Agonist binding may occur on a particular subunit that may be represented more than once in the assembled multimer (e.g., the nicotinic acetylcholine receptor) or may be conferred by a separate single subunit of the assembled channel, as is the case with the sulfonylurea receptor (SUR) that associates with a K+ channel (Kir62) to regulate the ATP-dependent K+ channel (KATp) (see Chapter 60). Openers of the same channel (minoxidil) are used as vascular smooth muscle relaxants. Receptor-operated channels also are regulated by other receptor-mediated events, such as protein kinase activation following activation of G proteincoupled receptors (GPCRs) (see below). Phosphorylation of the channel protein on one or more of its subunits can confer both activation and inactivation depending on the channel and the nature of the phosphorylation.

G Protein-Coupled Receptors

A large superfamily of receptors that accounts for many known drug targets interacts with distinct heterotrimeric GTP-binding regulatory proteins known as G proteins. G proteins are signal transducers that convey information (i.e., agonist binding) from the receptor to one or more effector proteins. GPCRs include those for a number of biogenic amines, eicosanoids and other lipid-signaling molecules, peptide hormones, opioids, amino acids such as GABA, and many other peptide and protein ligands. G protein-regulated effectors include enzymes such as adenylyl cyclase, phospholipase C, phosphodiesterases, and plasma membrane ion channels selective for Ca2+ and K+ (Figure 1-7). Because of their number and physiological importance, GPCRs are the targets for many drugs; perhaps half of all nonantibiotic prescription drugs are directed toward these receptors that make up the third largest family of genes in humans.

GPCRs span the plasma membrane as a bundle of seven a-helices. G proteins, composed of a GTP-binding a subunit, which confers specific recognition by receptor and effector, and an associated dimer of b and g subunits that can confer both membrane localization of the G protein (e.g., via myristoylation) and direct signaling such as activation of inward rectifier K+ (GIRK) channels and binding sites for G protein receptor kinases (GRKs), bind to the cytoplasmic face of the receptors promoting the binding of GTP to the G protein a subunit. GTP activates the G protein and allows it, in turn, to activate the effector protein. The G protein remains active until it hydrolyzes the bound GTP to GDP. Activation of the Ga subunit by GTP allows it to regulate an effector protein and to drive the release of Gpg subunits, which can also regulate effectors (e.g., K+ channels), and which ultimately reassociate with GDP-liganded Ga, returning the system to the basal state.

Central to the effect of many GPCRs is release of Ca2+from intracellular stores. For example, a receptors for norepinephrine activate G specific for the activation of phospholipase C^ Phospholipase C„ (PLC^ is a membrane-bound enzyme that hydrolyzes a membrane phospholipid, phosphatidylinositol-4,5-bisphosphate, to generate inositol-1,4,5-trisphosphate (IP) and the lipid, diacylglycerol. IP3 binds to receptors on Ca2+ release channels in the IP ^-sensitive Ca2+ stores of the endoplasmic reticulum, triggering the release of Ca2+ and rapidly raising [Ca2+].. The elevation of [Ca2+]. is transient owing to its avid reuptake into stores. Ca2+ can bind to and directly regulate ion channels (e.g., large conductance Ca2+-activated K+ channels). Ca2+ can also bind to calmodulin; the resulting Ca2+-calmodulin complex then can modulate a variety of effectors, including ion channels (e.g., the small conductance Ca2+-activated K+ channels), and cellular enzymes (e.g., Ca2+-calmodulin-dependent protein kinases and PDEs).

Receptor-ligand interactions alone do not regulate all GPCR signaling. It is now clear that GPCRs undergo both homo- and heterodimerization and possibly oligomerization. Heterodimer-ization can result in receptor units with altered pharmacology compared with either individual receptor. Evidence is emerging that dimerization of receptors may regulate the affinity and specificity of the complex for G protein and regulate the sensitivity of the receptor to phosphorylation by receptor kinases and the binding of arrestin, events important in termination of the action of agonists and removal of receptors from the cell surface. Dimerization also may permit binding of receptors to other regulatory proteins such as transcription factors. Thus, the receptor-G protein effector systems are complex networks of convergent and divergent interactions involving both receptor-receptor and receptor-G protein coupling that permits extraordinarily versatile regulation of cell function.

Transcription Factors

Receptors for steroid hormones, thyroid hormone, vitamin D, and the retinoids are soluble DNA-binding proteins that regulate the transcription of specific genes. These receptors act as both hetero- and homo-dimers with homologous cellular proteins, but may be regulated by higherorder oligomerization with other modulators, often bound to these modulatory proteins in the cytoplasm, retaining them in an inactive state. Regulatory sites in DNA where agonists bind are receptor-specific: the sequence of a "glucocorticoid-response element," with only slight variation, is associated with each glucocorticoid-response gene, whereas a "thyroid-response element" confers specificity of the actions of the thyroid hormone nuclear receptor.

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