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The Journal of Neuroscience, December 1, 2004, 24(48):10980-10992; doi:10.1523/JNEUROSCI.3869-04.2004

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Cellular/Molecular
Phosphotidylinositol 4,5-Bisphosphate Signals Underlie Receptor-Specific G_q/11-Mediated Modulation of N-Type Ca²⁺ Channels

Nikita Gamper,¹ Vitaliy Reznikov,¹ Yoichi Yamada,² Jian Yang,² and Mark S. Shapiro¹

¹Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, and ²Department of Biological Sciences, Columbia University, New York, New York 10027

Modulation of voltage-gated Ca²⁺ channels via G-protein-coupled receptors is a prime mechanism regulating neurotransmitter release and synaptic plasticity. Despite extensive studies, the molecular mechanism underlying G_q/11-mediated modulation remains unclear. We found cloned and native N-type Ca²⁺ channels to be regulated by phosphotidylinositol 4,5-bisphosphate (PIP₂). In inside-out oocyte patches, PIP₂ greatly attenuated or reversed the observed rundown of expressed channels. In sympathetic neurons, muscarinic M₁ ACh receptor suppression of the Ca²⁺ current (I_Ca) was temporally correlated with PIP₂ hydrolysis, blunted by PIP₂ in whole-cell pipettes, attenuated by expression of PIP₂-sequestering proteins, and became irreversible when PIP₂ synthesis was blocked. We also probed mechanisms of receptor specificity. Although bradykinin also induced PIP₂ hydrolysis, it did not inhibit I_Ca. However, bradykinin receptors became nearly as effective as M₁ receptors when PIP₂ synthesis, IP₃ receptors, or the activity of neuronal Ca²⁺ sensor-1 were blocked, suggesting that bradykinin receptor-induced intracellular Ca²⁺ increases stimulate PIP₂ synthesis, compensating for PIP₂ hydrolysis. We suggest that differential use of PIP₂ signals underlies specificity of G_q/11-coupled receptor actions on the channels.

Key words: calcium channel; muscarinic receptor; lipid signaling; bradykinin, G-protein; patch clamp

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Received Sep 17, 2004; revised October 20, 2004; accepted October 22, 2004.

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