Signaling mechanisms of down-regulation of voltage-activated Ca2+ channels by transient receptor potential vanilloid type 1 stimulation with olvanil in primary sensory neurons

Z. Z. Wu, S. R. Chen, H. L. Pan

Research output: Contribution to journalArticlepeer-review

Abstract

Olvanil ((N-vanillyl)-9-oleamide), a non-pungent transient receptor potential vanilloid type 1 agonist, desensitizes nociceptors and alleviates pain. But its molecular targets and signaling mechanisms are little known. Calcium influx through voltage-activated Ca2+ channels plays an important role in neurotransmitter release and synaptic transmission. Here we determined the effect of olvanil on voltageactivated Ca2+ channel currents and the signaling pathways in primary sensory neurons. Whole-cell voltage-clamp recordings were performed in acutely isolated rat dorsal root ganglion neurons. Olvanil (1 μM) elicited a delayed but sustained inward current, and caused a profound inhibition (~60%) of N-, P/Q-, L-, and R-type voltage-activated Ca2+ channel current. Pretreatment with a specific transient receptor potential vanilloid type 1 antagonist or intracellular application of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid abolished the inhibitory effect of olvanil on voltageactivated Ca2+ channel current. Calmodulin antagonists (ophiobolin-A and calmodulin inhibitory peptide) largely blocked the effect of olvanil and capsaicin on voltage-activated Ca2+ channel current. Furthermore, calcineurin (protein phosphatase 2B) inhibitors (deltamethrin and FK-506) eliminated the effect of olvanil on voltage-activated Ca2+ channel current. Notably, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, calmodulin antagonists, and calcineurin inhibitors each alone significantly increased the amplitude of voltage-activated Ca2+ channel current. In addition, double immunofluorescence labeling revealed that olvanil induced a rapid internalization of CaV2.2 immunoreactivity from the membrane surface of dorsal root ganglion neurons. Collectively, this study suggests that stimulation of nonpungent transient receptor potential vanilloid type 1 inhibits voltage-activated Ca2+ channels through a biochemical pathway involving intracellular Ca2+-calmodulin and calcineurin in nociceptive neurons. This new information is important for our understanding of the signaling mechanisms of desensitization of nociceptors by transient receptor potential vanilloid type 1 analogues and the feedback regulation of intracellular Ca2+ and voltage-activated Ca2+ channels in nociceptive sensory neurons.

Original languageEnglish (US)
Pages (from-to)407-419
Number of pages13
JournalNeuroscience
Volume141
Issue number1
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

Keywords

  • Calmodulin
  • Dorsal root ganglia
  • Nociceptors
  • Protein phosphatase 2B

ASJC Scopus subject areas

  • Neuroscience(all)

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