Transient receptor potential vanilloid type 1 activation down-regulates voltage-gated calcium channels through calcium-dependent calcineurin in sensory neurons

Zi Zhea Wu, Shao Rui Chea, Hui Lin Pan

Research output: Contribution to journalArticlepeer-review

Abstract

Calcium influx through voltage-activated Ca2+ channels (VACCs) plays a critical role in neurotransmission. Capsaicin application inhibits VACCs and desensitizes nociceptors. In this study, we determined the signaling mechanisms of the inhibitory effect of capsaicin on VACCs in primary sensory neurons. Whole-cell voltage clamp recordings were performed in acutely isolated rat dorsal root ganglion neurons. Capsaicin caused a profound decrease in the Ca2+ current (ICa) density in capsaicin-sensitive, but not -insensitive, dorsal root ganglion neurons. At 1 μM, capsaicin suppressed about 60% of N-, P/Q-, L-, and R-type ICa density. Pretreatment with iodoresiniferatoxin, a specific transient receptor potential vanilloid type 1 (THPV1) antagonist, or intracellular application of 1,2-bis(2-aminophenoxy) ethane-N,N,N′N′-tetraacetic acid blocked the inhibitory effect of capsaicin on ICa. However, neither W-7, a calmodulin blocker, nor KN-93, a CaMKII inhibitor, attenuated the inhibitory effect of capsaicin on ICa. Furthermore, intracellular dialysis of deltamethrin or cyclosporin A, the specific calcineurin (protein phosphatase 2B) inhibitors, but not okadaic acid (a selective protein phosphatase 1/protein phosphatase 2A inhibitor), abolished the effect of capsaicin on ICa. Interestingly, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, deltamethrin, cyclosporin A, and okadaic acid each alone significantly increased the ICa density and caused a depolarizing shift in the voltage dependence of activation. Immunofluorescence labeling revealed that capsaicin induced a rapid internalization of Cav2.2 channels on the membrane. Thus, this study provides novel information that VACCs are tonically modulated by the intracellular Ca2+ level and endogenous pliosphatases in sensory neurons. Stimulation of TBPV1 by capsaicin down-regulates VACCs by dephosphorylation through Ca2+-dependent activation of calcineurin.

Original languageEnglish (US)
Pages (from-to)18142-18151
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number18
DOIs
StatePublished - May 6 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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