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A mechanistic role for polypeptide hormone receptor lateral mobility in signal transduction

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Summary

Lateral diffusion of membrane-integral receptors within the plane of the membrane has been postulated to be mechanistically important for signal transduction. Direct measurement of polypeptide hormone receptor lateral mobility using fluorescence photobleaching recovery techniques indicates that tyrosine kinase receptors are largely immobile at physiological temperatures. This is presumably due to their signal transduction mechanism which requires intermolecular autophosphorylation through receptor dimerization and thus immobilization for activation. In contrast, G-protein coupled receptors must interact with other membrane components to effect signal transduction, and consistent with this, the phospholipase C-activating vasopressin V1- and adenylate cyclase activating V2-receptors are highly laterally mobile at 37°C. Modulation of the V2-receptor mobile fraction (f) has demonstrated a direct correlation between f and receptor-agonist-dependent maximal cAMP productionin vivo at 37°C. This indicates that f is a key parameter in hormone signal transduction especially at physiological hormone concentrations, consistent with mobile receptors being required to effect V2-agonist-dependent activation of G-proteins. Measurements using a V2-specific antagonist show that antagonist-occupied receptors are highly mobile at 37°C, indicating that receptor immobilization is not the basis of antagonism. In contrast to agonist-occupied receptor however, antagonistoccupied receptors are not immobilized prior to endocytosis and down-regulation. Receptors may thus be freely mobile in the absence of agonistic ligand; stimulation by hormone agonist results in receptor association with other proteins, probably including cytoskeletal components, and immobilization. Receptor immobilization may be one of the important steps of desensitization subsequent to agonistic stimulation, through terminating receptor lateral movement which is instrumental in generating and amplifying the initial stimulatory signal within the plane of the membrane.

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Abbreviations

FBR:

fluorescence photobleaching recovery

EGF:

epidermal growth factor

AC:

adenylate cyclase

D:

apparent lateral diffusion coefficient

f:

mobile fraction

G-:

GTP-binding protein

Gs:

stimulatory G-protein

TKR:

tyrosine kinase receptor

PDGF:

platelet-derived growth factor

IL:

interleukin

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  1. Nuclear Signalling Laboratory, Division for Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, P.O. Box 334, A.C.T. 2601, Canberra City, Australia

    D. A. Jans

  2. Institute for Medical Chemistry, Szeged Medical University, Szeged, Hungary

    I. Pavo

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Jans, D.A., Pavo, I. A mechanistic role for polypeptide hormone receptor lateral mobility in signal transduction. Amino Acids 9, 93–109 (1995). https://doi.org/10.1007/BF00805831

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