4.7 Article

Phosphotidylinositol 4,5-bisphosphate signals underlie receptor-specific Gq/11-mediated modulation of N-type Ca2+ channels

Journal

JOURNAL OF NEUROSCIENCE
Volume 24, Issue 48, Pages 10980-10992

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3869-04.2004

Keywords

calcium channel; muscarinic receptor; lipid signaling; bradykinin; G-protein; patch clamp

Categories

Funding

  1. NINDS NIH HHS [R01 NS043394, R01 NS43394, R01 NS045819] Funding Source: Medline

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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 M-1 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 M-1 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.

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