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The Journal of Neuroscience, September 27, 2006, 26(39):9983-9995; doi:10.1523/JNEUROSCI.2773-06.2006

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Cellular/Molecular
Modulation of G_q-Protein-Coupled Inositol Trisphosphate and Ca²⁺ Signaling by the Membrane Potential

Daniela Billups, Brian Billups, R. A. John Challiss, and Stefan R. Nahorski

Department of Cell Physiology and Pharmacology, Medical Sciences Building, University of Leicester, Leicester LE1 9HN, United Kingdom

Correspondence should be addressed to Daniela Billups, Department of Cell Physiology and Pharmacology, Medical Sciences Building, University of Leicester, University Road, Leicester LE1 9HN, UK. Email: db84{at}le.ac.uk

G_q-protein-coupled receptors (G_qPCRs) are widely distributed in the CNS and play fundamental roles in a variety of neuronal processes. Their activation results in phosphatidylinositol 4,5-bisphosphate (PIP₂) hydrolysis and Ca²⁺ release from intracellular stores via the phospholipase C (PLC)–inositol 1,4,5-trisphosphate (IP₃) signaling pathway. Because early G_qPCR signaling events occur at the plasma membrane of neurons, they might be influenced by changes in membrane potential. In this study, we use combined patch-clamp and imaging methods to investigate whether membrane potential changes can modulate G_qPCR signaling in neurons. Our results demonstrate that G_qPCR signaling in the human neuronal cell line SH-SY5Y and in rat cerebellar granule neurons is directly sensitive to changes in membrane potential, even in the absence of extracellular Ca²⁺. Depolarization has a bidirectional effect on G_qPCR signaling, potentiating thapsigargin-sensitive Ca²⁺ responses to muscarinic receptor activation but attenuating those mediated by bradykinin receptors. The depolarization-evoked potentiation of the muscarinic signaling is graded, bipolar, non-inactivating, and with no apparent upper limit, ruling out traditional voltage-gated ion channels as the primary voltage sensors. Flash photolysis of caged IP₃/GPIP₂ (glycerophosphoryl-myo-inositol 4,5-bisphosphate) places the voltage sensor before the level of the Ca²⁺ store, and measurements using the fluorescent bioprobe eGFP–PH_PLC (enhanced green fluorescent protein–pleckstrin homology domain–PLC) directly demonstrate that voltage affects muscarinic signaling at the level of the IP₃ production pathway. The sensitivity of G_qPCR IP₃ signaling in neurons to voltage itself may represent a fundamental mechanism by which ionotropic signals can shape metabotropic receptor activity in neurons and influence processes such as synaptic plasticity in which the detection of coincident signals is crucial.

Key words: voltage; G-protein-coupled receptor; calcium; inositol 1,4,5-trisphosphate; membrane potential; muscarinic acetylcholine receptor

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Received March 24, 2006; revised Aug. 4, 2006; accepted Aug. 10, 2006.

Correspondence should be addressed to Daniela Billups, Department of Cell Physiology and Pharmacology, Medical Sciences Building, University of Leicester, University Road, Leicester LE1 9HN, UK. Email: db84{at}le.ac.uk

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