Structural heterogeneity of membrane receptors and GTP-binding proteins and its functional consequences for signal transduction

Abstract

Recent information obtained, mainly by recombinant cDNA technology, on structural heterogeneity of hormone and transmitter receptors, of GTP-binding proteins (G-proteins) and, especially, of G-protein-linked receptors is reviewed and the implications of structural heterogeneity for diversity of hormone and transmitter actions is discussed. For the future, three-dimensional structural analysis of membrane proteins participating in signal transmission and transduction pathways is needed in order to understand the molecular basis of allosteric regulatory mechanisms governing the interactions between these proteins including hysteretic properties and cellcybernetic aspects.Thanks to recombinant DNA technology, there has been a recent flood of structural information on membrane receptors, G-proteins and target enzymes [for reviews see Gilman

Thrombin‐induced proliferation and expression of platelet‐derived growth factor‐A chain gene in human vascular smooth muscle cells

“…3) suggesting synergism via several mechanisms of signal transduction0 and/or that potentiation may depend on the level of concentration of second messenger(s) induced by thrombin. These observations are in agreement with the evidence in support of cooperative effects on cell proliferation of G protein-dependent signal pathways and growth factor-receptor tyrosine kinases [42] and the fact that thrombin and endothelin have similar mitegenie and vasoconstrictor activities in SMC [17,43].…”

Differential G protein subunit expression by prostate cancer cells and their interaction with CXCR5

“…Evidence also supports the ability of CCR5 to interact with non-chemokine receptors including opioid receptors [49]. While CXCR4 is present in almost all invasive cancers, CXCR5 has been implicated in advanced stages of chronic myelogenous leukemia, head and neck cancers, colon, and prostate cancer [1,12,29,50]. There is growing evidence to suggest transactivation of chemokine receptors will result in signal amplification at the receptor level, providing a means for tumor cells to metastasize and grow [21,46].…”

“…G protein-coupled receptors (GPCRs) are divided into three broad classes based on the similarity of the transmembrane sequences and the nature of their ligand [1]. Chemokine receptors are categorized under the superfamily of Class A Rhodopsin-like GPCRs [2].…”

“…After ligand binding, the receptor elicits a conformational alteration resulting in the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) by the G α subunit. This leads to heterotrimer dissociation and stimulation of downstream effector molecules to initiate intracellular signaling cascades [1,3,4]. G α subunits are divided into four families G αs , G αi , G αq/11 , and G α12/13 based on sequence homology and functional similarities.…”

Structural flexibility of small GTPases. Can it explain their functional versatility?

“…The first model describing such a situation is the widely known 'allosteric' Monod-Wyman-Changeux (MWC) model (Monod et al, 1965). These include G protein-coupled receptors (Boege et al, 1991;George et al, 2002) and many other types of receptors and receptor-like membrane-bound proteins, such as the integrins, which participate in a multitude of interactions (Gottschalk and Kessler, 2002). This may result in inactivation or activation of the protein.…”