Mini-reviewG-protein-coupled receptors, tyrosine kinases and neurotransmission
Introduction
Phosphorylation is a rapid and versatile form of post-translational protein modification, which is particularly suited to the modulation of ion channel activity in neuronal information processing. Because channel phosphorylation outlasts the initiating stimulus, the cell now has a record of a past event, or a memory, whose readout can be observed as a change in membrane properties. The regulation of neuronal responses by protein phosphorylation is generally induced through the actions of neurotransmitters and trophic factors. Research over the past two decades has shown that the activation of G-protein-coupled (metabotropic) receptors triggers intracellular signaling pathways that control enzyme activity usually via phosphorylation or dephosphorylation of serine and threonine residues, whereas the activation of cell surface receptors by trophic factors initiates transduction cascades associated with G-protein-independent kinases that target tyrosine residues. Based on the differences in these two modes of intracellular transduction, the classical view has been that neurotransmitter-induced activation of enzymatic cascades mediates primarily fast neuronal responses in the tens to hundreds of milliseconds range, while trophic responses are associated with slower but long lasting changes important for cellular survival, proliferation, and differentiation.
Several recent studies have shown, however, that diverse neurotransmitters also activate tyrosine kinase-dependent signaling pathways (Boxall and Lancaster, 1998, Marinissen and Gutkind, 2001) and conversely, that stimulation of receptor tyrosine kinases can gate the activity of ion channels (Rane, 1999, Schinder and Poo, 2000). This brief review focuses on a selection of studies that provide evidence for tyrosine kinase signaling by neurotransmitters activating G-protein-coupled receptors, and presents findings from biochemical studies on tyrosine phosphorylation with potential significance for neuronal function (Fig. 1).
Following the original discovery of protein tyrosine phosphorylation (Eckhart et al., 1979), rapid advances led to the identification of numerous receptor tyrosine kinases, which are cell surface receptors with integral catalytic domains, and non-receptor tyrosine kinases, which associate with receptors lacking intrinsic kinase activity (Hunter and Cooper, 1985). Tyrosine kinase activation via G-protein-coupled receptors was suggested by the observation of a block of mitogenic effects following G-protein inhibition by pertussis toxin treatment (Pouyssegur et al., 1988). The first indication in the nervous system that tyrosine kinase signaling could result from stimulation of G-protein coupled receptors was obtained in experiments in which activation of the muscarinic acetylcholine receptor in hippocampal slices was found to increase tyrosine phosphorylation of a cytosolic protein (Stratton et al., 1989). Subsequent investigations have characterized G-protein-coupled receptor actions via tyrosine kinases in terms of receptor mechanisms, intracellular transduction pathways, and effectors mediating neuronal responses.
Section snippets
Tyrosine kinase-dependent signaling through G-protein coupled receptors
When expressed in heterologous systems most, if not all, G-protein-coupled receptors involved in synaptic transmission can be shown to direct downstream tyrosine kinase signaling in addition to their more familiar actions via adenylyl cyclases, phospholipases, or ion channels (Marinissen and Gutkind, 2001). Because G-protein-coupled receptors do not directly interact with membrane ion channels and second messenger-producing enzymes, transduction systems have evolved to link the receptors with
G-protein-independent transduction
A diversity of observations in non-neuronal cells has established that G-protein-coupled receptors can also transduce cellular signals through G-protein-independent pathways (Hall et al., 1999, Miller and Lefkowitz, 2001). A crucial step in these alternative modes of metabotropic transduction appears to be the binding of arrestin to the receptor. This adapter protein then organizes a scaffold of proteins signaling through tyrosine kinase cascades. β-arrestin has been well characterized as a key
Tyrosine kinase targets
It is clear that mechanisms allowing synaptic receptors to feed into tyrosine kinase transduction cascades would greatly broaden the spectrum of neurotransmitter actions. Molecular approaches have identified a multitude of intracellular targets for tyrosine kinases, but only few studies have examined the consequences of neurotransmitter-induced tyrosine phosphorylation on neuronal function. A straightforward and rapid way of modulating synaptic transmission through tyrosine kinases is by
Tyrosine kinases and plasticity
Beginning with the report by O’Dell and colleagues (1991), which showed that tyrosine kinase inhibitors blocked the induction of hippocampal long term potentiation (LTP), the potential roles of tyrosine kinases in synaptic plasticity phenomena have become the focus of intense investigation. A series of reports by the laboratories of Salter and of MacDonald has shown that upregulation of NMDA receptor function by Src phosphorylation (Fig. 2) considerably facilitates the induction of LTP (Ali and
Conclusion
The finding that stimulation of G-protein-coupled receptors induces tyrosine kinase activity presents exciting new perspectives in the field of synaptic signaling. A major challenge will be to identify the physiologically relevant transduction pathways from among the multitudes of recently discovered new signaling proteins (Milligan and White, 2001). Furthermore, as neuronal G-protein-coupled receptors are unlikely to be activated in isolation except in the laboratory, future studies will have
Acknowledgments
I am grateful to P. Benquet, B. Gähwiler, C. Gee, C. Heuss, and M. Scanziani for critical comments on the manuscript and E. Hochreutener for preparation of figures. The author receives support from the Swiss National Science Foundation and the NCCR on Neural Plasticity and Repair.
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