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

By N. Gamper, Vitaliy Reznikov, Yoichi Yamada, Jian Yang, M. Shapiro. Journal of Neuroscience, 2004

202 citations recorded by the source corpus.

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 Gq/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 (ICa) 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 ICa. 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 Gq/11-coupled receptor actions on the channels.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c85ad58e66483179afa746eb305a254afe16c09b

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1. Maria P. Abbracchio
2. Geoffrey Burnstock
3. Jean-Marie Boeynaems
4. Eric A. Barnard
5. Jose L. Boyer
6. Charles Kennedy
7. M. Fumagalli
8. Gary A. Weisman

Citations in the corpus

• International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy (2006, background): “The same PIP2/PI4-kinase mechanism has been supported for the closure of the N-type Ca2 channel by similar observations on Gq-linked muscarinic M1 receptor action and its recovery (Gamper et al., 2004).”
• Pathways modulating neural KCNQ/M (Kv7) potassium channels (2005, unknown): “Indeed, in some elegant experiments, Gamper et al”