Trends in Pharmacological Sciences
G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways
Section snippets
Fine-tuning of GPCR signals
Stimulation of GPCRs, which couple to second- messenger generation via multiple heterotrimeric G proteins (consisting of Gα and Gβγ subunits), can result in `direct' effects on a range of signalling proteins, including phospholipase C (PLC), adenylate cyclase and ion channels[6] (see, for example, Fig. 1). GPCR stimulation causes dissociation of G protein subunits following the binding of GTP to Gα; this can subsequently result in the activation of distinct Gα- and Gβγ-sensitive isoforms of
Cross-talk between Gs- and Gq-coupled receptors
Finally, cross-talk between Gs- and Gq-coupled receptors has also been observed (Fig. 3). While Gq-coupled-receptor activation stimulates production of inositol phosphates, it can also augment Gs-coupled-receptor stimulation of adenylate cyclase activity. The augmentation may, in some examples, be mediated by PKC activity, since phorbol esters potentiate neurotransmitter-stimulated cAMP accumulation in brain slices[34], and PKC inhibitors block α1-adrenoceptor- and phorbol ester- mediated
Influence of constitutive activation on integration of signals
Many `silent' GPCR agonists, which have little effect on their own, can stimulate measurable receptor function only when assayed in the presence of coincident activation of a GPCR that mediates more direct or pronounced effects on particular second messengers. For example, the Gβγ-subunit-mediated stimulation of adenylate cyclase by Gαq-coupled receptors requires co-stimulation of Gαs ([10]), and a similar mechanism appears to operate for Gαq and PLC activity[32]. However, a requirement for
Integration with other receptor classes
In addition to interactions between different GPCR signal-transduction pathways, GPCRs also interact with other receptor classes. The actions of receptor tyrosine kinase signalling pathways, which can result in effects on cellular proliferation and cytoskeletal effects such as contraction, are particularly relevant (Appendix B). GPCR function may be modulated by receptor tyrosine kinase-mediated GPCR phosphorylation. For example, NPY, adenosine and 5-HT receptors have conserved tyrosine
Implications for drug development
Recent therapeutic development has been directed at the identification of multiple receptor subtypes and their specific direct actions in attempts to develop agonists and antagonists with fewer side-effects. However, the indirect or synergistic effects of many neuromodulators and neurotransmitters, particularly those coupled to Gi proteins, may represent a potential source of novel therapeutic approaches. The cross-talk of intracellular mechanisms also raises important issues regarding data
Concluding remarks
When signals are transmitted from cell surface to nucleus, it appears that relatively small changes in the production of second messengers can be amplified by coincident receptor activation. Such signals can converge at sites further downstream with signalling pathways stimulated by other receptor classes. The expanding numbers of GPCRs that are being identified by gene cloning and the availability of more discriminatory pharmacological agents is being matched by an increasing awareness of the
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