[Frontiers in Bioscience 3, d769-780, August 1, 1998]

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Wayne B. Bowler1, James A. Gallagher and Graeme Bilbe2

1 Human Bone Cell Research Group, Department of Human Anatomy and Cell Biology, University of Liverpool, England, L69 3GE 2 Novartis Pharma A.G., Postfach, K681.4.43, CH-4002 Basel, Switzerland

Received 1/16/98 Accepted 2/17/98


The seven transmembrane domain receptors belong to a superfamily of functionally diverse receptors all sharing integral hydrophobic membrane spanning domains, separated by alternating extracellular and intracellular hydrophilic loops. Receptors belonging to this class respond to a variety of hormone and neurotransmitter agonists ranging from small biogenic amines such as adrenaline, to large peptides such as parathyroid hormone (PTH) and calcitonin. Ligand binding is facilitated by the formation of a pocket between specific` extracellular and transmembrane domains (16), within which conserved amino acid residues determine the ligand specificity and affinity for families of receptors. Binding of ligand to its receptor induces a conformational change resulting in the formation of a high affinity ligand-G-protein complex which catalyses guanine nucleotide exchange on the alpha subunit of the G-protein. The G-proteins dissociate from the receptor-ligand complex and transduce the extracellular signal from the receptor to a variety of intracellular signaling pathways. For excellent reviews on these processes see (23) and (84). The complex receptor-G-protein interaction occurs through a surface on the cytoplasmic side of the receptor composed of the ends of the transmembrane domains and the intracellular loops. This interaction predominantly involves the third intracellular loop, although mutational analyses have shown that specific residues in any of the intracellular loops or the C terminal tail contribute to the G-protein interaction (83). Receptor desensitization or downregulation occurs following repeated or sustained activation, providing a feedback mechanism limiting receptor activity. Such desensitization involves receptor phosphorylation by numerous kinases including, protein kinase A (PKA) and C (PKC) and by receptor specific kinases, including beta-adrenergic receptor kinase, BARK (3). Long term exposure to ligand can result in changes to transcriptional activity and ultimately receptor down regulation.