Functional organization of PLC signaling microdomains in neurons

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Abstract

Our understanding of receptor transduction systems has grown impressively in recent years as a result of intense efforts to characterize signaling molecules and cascades in neurons. A large body of evidence has recently accrued regarding the fast and effective signal transfer that occurs during phosphoinositide signaling. In particular, dissection of the Drosophila phototransduction pathway has enabled a greater understanding of the molecular organization of phospholipase C (PLC) signaling. Supramolecular complexes organize the correct repertoires of receptors, enzymes and ion channels into individual signaling pathways. Such mechanisms involve localization of signaling molecules to sites of action by scaffold and anchoring proteins, ensuring speed and specificity of signal transduction events. However, not all PLC signals nucleate around scaffold proteins, although mechanisms for selectivity and discrimination remain. This article reviews recent advances on the molecular organization and functional consequences of PLC signaling domains, which link membrane receptors to ion channels, including TRP and KCNQ channels.

Section snippets

PLC-mediated signaling to TRP channels: an example of receptor–ion-channel segregation

The sophistication of PLC signaling is best illustrated by the phototransduction cascade in the fruitfly Drosophila 3, 4, 5. This PLCβ-coupled mechanism represents the fastest Gq-protein-signaling pathway known: the absorption of a single photon by rhodopsin is translated into a physiological response (a depolarization) in just 20 ms [6]. Nonetheless, phototransduction in flies is a complex, multiprotein cascade involving many enzymatic processes. First, light signal is transmitted from the Gαq

PLC-mediated signaling to KCNQ/M channels: an example of receptor segregation

Neural KCNQ/M channels can be shut down by virtually any Gαq–PLC- or Gα11–PLC-coupled receptor 40, 41. Indeed, all of their putative subunits (KCNQ2–5) – and even the cardiac homolog KCNQ1 – appear to be equally susceptible to suppression by an appropriate Gαq- or Gα11-linked G-protein-coupled receptor [42]. Nevertheless, there seems to be some functional discrimination between different receptors, at least mechanistically.

Thus, KCNQ/M channels in sympathetic neurons are closed by ACh (the

Concluding remarks: new principles for PLC signaling

Because the PLCβ cascade is utilized by a large numbers of transmembrane receptors and is present in virtually all cells, a central question is how these cells generate receptor-specific signals. From the two examples discussed here, it appears that PLC signaling pathways are tightly coupled, forming architecturally distinct signaling complexes or microdomains. Two strategies also seem to emerge. In the first model, exemplified by the Drosophila phototransduction, the PLC signaling complex

Acknowledgements

Our work was supported by the Centre National de la Recherche Scientifique (CNRS) and by grants from the UK Medical Research Council and the Wellcome Trust.

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