Receptor Biochemistry And Signal Transduction

A receptor (Hulme, 1990; Strader et al., 1994) is a molecule (commonly biomac-romolecule) in/on a cell that specifically recognizes and binds a ligand acting as a signal molecule. Ligand - receptor interactions constitute important initial steps in various cellular processes. The ligands such as hormones and neurotransmitters bind to plasma membrane receptors, which are transmembrane glycoproteins. These ligands include bioactive amines (acetylcholine, adrenaline, dopamine, histamine, serotonin), peptides (calcitonin, glucagon, secretin, angiotensin, bradykinin, inter-leukin, chemokine, endothelin, melanocortin, neuropeptide Y, neurotensin, somatostatin, thrombin, galanin, orexin), hormone proteins, prostaglandin, adenosine, and platelet activating factor. Other ligands such as steroids and thyroid hormones bind soluble DNA-binding proteins. The ligand-receptor interactions initiate various signal transduction (Heldin and Purton, 1996; Milligan, 1999) pathways that mobilize second messengers which activate/inhibit cascade of enzymes and proteins involved in specific cellular processes (Gilman, 1987; Hepher and Gilman, 1992; Hollenberg, 1991; Kaziro et al., 1991). Three membrane receptor groups that mediate eukaryotic transmembrane signaling processes are as follows:

1. Group 1, Single-transmembrane segment catalytic receptors: Proteins consisting of a single transmembrane segment with (a) a globular extracellular domain, which is the ligand recognition site, and (b) an intracellular catalytic domain, which is either tyrosine kinase or guanylyl cyclase.

2. Group 2, Seven-transmemebrane segment receptors: Integral membrane pro teins consisting of seven transmembrane helical segments with extracellular recognition site for ligands and an intracellular recognition site for a GTP-binding protein.

3. Group 3, Oligomeric ion channels: Ligand-gated ion channels consisting of associated protein subunits that contain several transmembrane segments. Typically, the ligands are neurotransmitters that open the ion channels upon binding.

The binding of these receptors with many ligands stimulates a G-protein (GTP-binding protein), which in turn activates an effector enzyme (e.g., adenylyl cyclae/phospholipase C). Typically, G-proteins (Gilman, 1987; Kaziro et al., 1991; Strader et al., 1994) are heterotrimers (Ga^y) consisting of a-(Ga), ^-(G^), and y-(G7) subunits. Binding of the ligand to receptor stimulates an exchange of GTP for bound GDP on Ga causing Ga to dissociate from GaPy and to associate with an effector enzyme which synthesizes the second messenger (Ross and Wilkie, 2000). G-Proteins are a universal means of signal transduction in higher organisms, activating many hormone-receptor-initiated cellular processes via activation of adenylyl cyclases, phospholipases A/C, phosphodiesterases, and ion (Ca2 + , Na+, K+) channels. Each hormone receptor protein interacts specifically with either a stimulatory G protein or an inhibitory G protein. Some of G proteins and their physiological effects (Clapnam, 1996) are given in Table 6.1.

Two stages of amplification occur in the G-protein-mediated signal response. First, a single ligand-receptor complex can activate many G proteins. Second, the G-protein-activated adenylyl cyclase or phospholipase synthesizes many second messenger molecules. Some of these intracellular second messengers and their effects are given in Table 6.2.

Cyclic AMP (cAMP) is produced from ATP by the action of an integral membrane enzyme, adenylyl cyclase. Various second messengers, such as inositol-1,4,5-triphosphate, diacylglycerol, and arachidonic acid, are generated via breakdown of membrane phospholipids by the action of phospholipases (Liskovich, 1992). Calcium ion is an important intracellular signal (Carafoli and Klee, 1999) that is affected by either cAMP or inositol-1,4,5-triphosphate. The Ca2+ signals are translated into the desired intracellular response by calcium binding proteins (e.g., calmodulin, parvalbumin), which in turn regulate cellular processes via protein kinase C (PKC) (Ferrell, 1997). PKC is a cellular transducer, translating the ligand

TABLE 6.1. Some G Proteins and Their Physiological Effects
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