Transduction, transmembrane

The VACM-1 receptor is a membrane-associated protein with a single putative transmembrane domain that binds selectively AVP (XD — 2 nM), but cannot discriminate between VXR and V2R analogues. It is expressed in endothelial and medullary collecting duct cells and upon stimulation by AVP. It induces a mobilization of cytosolic-free Ca2+, decreases cAMP production and inhibits cellular growth via MAPK phosphorylation and p53 expression. The mechanism of action and physiological functions of this new receptor are not well understood, but it seems to participate in the regulation of AVP induced signal transduction pathways or of a yet unidentified peptide. 

Ganju RK, Brubaker SA, Meyer J, et al. The alpha-chemokine, stromal cell-derived factor-1 alpha, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J Biol Chem 1998 273(36) 23169-23175. 

Some cytokine receptors are composed of a single transmembrane polypeptide (e.g. receptors for IL-8, -9 and -10). Many contain two polypeptide components (including the IL-3, -4, and -5 receptors), and a few contain three or more polypeptide components (e.g. the IL-2 receptor contains three polypeptide chains). In some instances a single cytokine may be capable of initiating signal transduction by binding two or more distinct receptors (e.g. IL-1 has two distinct receptors (types I and II), both of which are transmembrane glycoproteins). 

The IFN-y receptor (the type II receptor) displays a more limited cellular distribution than that of the type I receptors (Table 8.5). This receptor is a transmembrane glycoprotein of molecular mass 50 kDa, which appears to function as a homodimer. The extracellular IFN-y binding region consists of approximately 200 amino acid residues folded into two homologous domains. Initiation of signal transduction also requires the presence of a second transmembrane glycoprotein known as AF-1 (accessory factor 1), which associates with the extracellular region of the receptor. 

Bitopic proteins with a single transmembrane helix are more common. If oriented with the N-terminus extra-cytoplasmic, they are classified as type I or, if cytoplasmic, type II (Fig. 2-4). Bitopic membrane proteins are often involved in signal transduction, as exemplified by receptor-activated tyrosine kinases (Ch. 24) agonist occupation of an extracytoplasmic receptor domain can transmit structural changes via a single transmembrane helix to activate the latent kinase activity in a cytoplasmic domain. 

The transmembrane domain in the RPTK is a hydrophobic segment of 22-26 amino acids inserted in the cell membrane. It is flanked by a proline-rich region in the N-terminus and a cluster of basic amino acids in the C-ter-minus. This combination of structures secures the transmembrane domain within the lipid bilayer. There is a low degree of homology in the transmembrane domain, even between two closely related RPTKs, suggesting that the primary sequence contains little information for signal transduction. 

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