Divergence of intracellular signalling

GPCR coupling to multiple G proteins is only one of the potential mechanisms accounting for the divergence of intracellular signalling in response to a single agonist. Taken together, these mechanisms (Figure 118) include:

• (A), agonist binding to different receptor subtypes, showing distinct G protein coupling specificities. Many monoamine-recognizing receptor subtypes have been

Figure 117 Effect of pertussis toxin (PTX) on UK-14,304-mediated stimulation of porcine a2-adrenergic receptors stably expressed in CHO cells at low (a2 -L) and high (a2 -H) densities. Reproduced from Brink, C. B., Wade, S. M. and Neubig, R. R. (2000) Journal of Pharmacology and Experimental Therapeutics, 294, 539-547, with permission from the American Society for Pharmacology and Experimental Theraputics.

Figure 117 Effect of pertussis toxin (PTX) on UK-14,304-mediated stimulation of porcine a2-adrenergic receptors stably expressed in CHO cells at low (a2 -L) and high (a2 -H) densities. Reproduced from Brink, C. B., Wade, S. M. and Neubig, R. R. (2000) Journal of Pharmacology and Experimental Therapeutics, 294, 539-547, with permission from the American Society for Pharmacology and Experimental Theraputics.

Figure 118 Different mechanisms accounting for the divergence of intracellular signalling in response to a single agonist. Reprinted from Pharmacology and Therapeutics, 99, Hermans, E., Biochemical and pharmacological control of the multiplicity of coupling at G protein-coupled receptors, 25-44, © (2003), with permission from Elsevier.

Figure 118 Different mechanisms accounting for the divergence of intracellular signalling in response to a single agonist. Reprinted from Pharmacology and Therapeutics, 99, Hermans, E., Biochemical and pharmacological control of the multiplicity of coupling at G protein-coupled receptors, 25-44, © (2003), with permission from Elsevier.

identified showing distinct G protein coupling specificities (e.g., 12 mammalian serotonin receptors, nine adrenergic receptors, etc.).

• (B), agonist binding to a single receptor, triggering the direct activation of distinct intracellular effectors through a single G protein. For example, once activated, both a and P-y subunits contribute to the modulation (in a synergistic or antagonistic fashion) of either same or unrelated effectors, resulting in dual intracellular signalling. The best-characterized example of such dual signalling through a single G protein is the Gi/o-mediated inhibition of adenylate cyclase (depending on the a subunit) and the stimulation of particular phospholipase C isoforms (depending on the P-y subunits). It is noteworthy that in this case P-y-related signals are frequently observed at higher agonist concentrations, probably reflecting the lower potency of these subunits in activating the effectors.

• (C), agonist binding to a single receptor that shows selectivity for a single intracellular effector through a single G protein, but divergence occurs at downstream levels in the signalling cascade.

• (D), agonist binding to a single receptor that mediates distinct signalling through direct interaction with multiple G proteins.

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