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Dual Regulation of R-Type Ca(V)2.3 Channels by M-1 Muscarinic Receptors

Dual Regulation of R-Type Ca(V)2.3 Channels by M-1 Muscarinic Receptors
Jeong, JY[Jeong, Jin-Young]Kweon, HJ[Kweon, Hae-Jin]Suh, BC[Suh, Byung-Chang]
DGIST Authors
Jeong, JY[Jeong, Jin-Young]; Kweon, HJ[Kweon, Hae-Jin]; Suh, BC[Suh, Byung-Chang]
Issue Date
Molecules and Cells, 39(4), 322-329
Article Type
AnimalAnimalsCalcium Channels, R-TypeCav2.3 ChannelCell MembraneChemistryDanio Rerio Voltage-Sensitive Phosphatase (Dr-VSP)Drug EffectsGene Expression RegulationHEK293 Cell LineHEK293 CellsHumanHumansM1 Muscarinic ReceptorMembrane PotentialMembrane PotentialsMetabolismMuscarinic M1 ReceptorPatch-Clamp TechniquePatch-Clamp TechniquesPhorbol 13 Acetate 12 MyristatePhosphatidylinositol 4,5-DiphosphatePhosphatidylinositol 4,5 BisphosphatePI(4,5)P2Protein Kinase C (PKC)PseudojaninReceptor, Muscarinic M1Tetradecanoylphorbol AcetateZebrafishZebrafish ProteinZebrafish Proteins
Voltage-gated Ca2+ (CaV) channels are dynamically modulated by G protein-coupled receptors (GPCR). The M1 muscarinic receptor stimulation is known to enhance CaV2.3 channel gating through the activation of protein kinase C (PKC). Here, we found that M1 receptors also inhibit CaV2.3 currents when the channels are fully activated by PKC. In whole-cell configuration, the application of phorbol 12- myristate 13-acetate (PMA), a PKC activator, potentiated CaV2.3 currents by ~two-fold. After the PMA-induced potentiation, stimulation of M1 receptors decreased the CaV2.3 currents by 52 ± 8%. We examined whether the depletion of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is responsible for the muscarinic suppression of CaV2.3 currents by using two methods: the Danio rerio voltagesensing phosphatase (Dr-VSP) system and the rapamycininduced translocatable pseudojanin (PJ) system. First, dephosphorylation of PI(4,5)P2 to phosphatidylinositol 4- phosphate (PI(4)P) by Dr-VSP significantly suppressed CaV2.3 currents, by 53 ± 3%. Next, dephosphorylation of both PI(4)P and PI(4,5)P2 to PI by PJ translocation further decreased the current by up to 66 ± 3%. The results suggest that CaV2.3 currents are modulated by the M1 receptor in a dual mode-that is, potentiation through the activation of PKC and suppression by the depletion of membrane PI(4,5)P2. Our results also suggest that there is rapid turnover between PI(4)P and PI(4,5)P2 in the plasma membrane. © The Korean Society for Molecular and Cellular Biology. All rights reserved.
Korean Society for Molecular and Cellular Biology
Related Researcher
  • Author Suh, Byung Chang Current Lab
  • Research Interests Molecular mechanisms of epilepsy and sensory pain transmission; Signaling mechanism of ion channel regulation and membrane excitability; 분자전기생리; 간질 및 통증의 분자적 기전 연구
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Department of Brain and Cognitive SciencesCurrent Lab1. Journal Articles

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