Trends in Neurosciences
Volume 23, Issue 10, 1 October 2000, Pages 469-475
Journal home page for Trends in Neurosciences

Review
G-protein-independent signaling by G-protein-coupled receptors

https://doi.org/10.1016/S0166-2236(00)01643-XGet rights and content

Abstract

Two classes of receptors transduce neurotransmitter signals: ionotropic receptors and heptahelical metabotropic receptors. Whereas the ionotropic receptors are structurally associated with a membrane channel, a mediating mechanism is necessary to functionally link metabotropic receptors with their respective effectors. According to the accepted paradigm, the first step in the metabotropic transduction process requires the activation of heterotrimeric G-proteins. An increasing number of observations, however, point to a novel mechanism through which neurotransmitters can initiate biochemical signals and modulate neuronal excitability. According to this mechanism metabotropic receptors induce responses by activating transduction systems that do not involve G-proteins.

Section snippets

G-proteins? Yes and no

No sooner had the essential role of G-proteins in transducing metabotropic responses been demonstrated5, 6, 7, than the first anomalous observation was published suggesting that metabotropic receptors can also induce responses through intracellular signaling pathways that do not require G-protein activation. This study, in 1988 by Olesen et al. reported G-protein-independent induction of a K+ current by ACh acting at muscarinic receptors in aortic endothelial cells8. However, this result was

G-protein independent signaling mechanisms

Although the current textbook view states that G-protein activation is a compulsory step in signal transduction by metabotropic receptors, identification of a growing number of receptor-binding proteins suggests alternative signaling mechanisms. Structurally, metabotropic receptors consist of an elongated protein chain traversing the cell membrane seven times, which has led to the additional terms, metabotropic or seven-transmembrane receptors. The highly conserved tertiary structure of

SRC kinase signaling

Cell growth and differentiation signals are mediated, in part, by a class of membrane receptors that do not exhibit intrinsic intracellular catalytic activity, but instead depend on activation of intracellular non-receptor tyrosine kinases to initiate responses. A central principle for this type of transduction is the recruitment of specific adaptor proteins that couple the activated receptor with the cytoplasmic tyrosine kinase23. Examples include receptors for various growth hormones,

Functional implications

The concept that metabotropic receptors are not restricted to intracellular signaling via G-proteins, but instead have access to alternate channels of intracellular communication, opens up a realm of additional functions for neurotransmitters. The convergence onto transduction pathways regulating trophic responses, such as MAP kinase activation, through SRC provides a platform for interactions with trophic factor signaling, through which neurotransmitters might directly contribute to cell

Concluding remarks

The established view that neurotransmitters and hormones, acting through metabotropic metabotropic receptors, mediate responses exclusively via G-protein-dependent signaling pathways is no longer tenable. Although G-protein activation is a key event in the majority of metabotropic receptor-mediated responses, alternative pathways coupled directly to the receptor might have similar importance for other responses. Molecular characterization of these alternative signaling pathways and the

Acknowledgements

The authors thank B. Gähwiler, M. Scanziani, D. Jabaudon, A. Lüthi and C. Fuhrer for valuable discussions. The author’s research is supported by the Swiss National Science Foundation (3100-059135.99) and the Prof. Dr Max Cloëtta. Foundation.

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