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J. Biol. Chem., Vol. 280, Issue 18, 18142-18151, May 6, 2005

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Transient Receptor Potential Vanilloid Type 1 Activation Down-regulates Voltage-gated Calcium Channels through Calcium-dependent Calcineurin in Sensory Neurons^*

Zi-Zhen Wu, Shao-Rui Chen, and Hui-Lin Pan, Recipient of a National Institutes of Health Independent Scientist Career Award

From the Department of Anesthesiology, Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

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 (I_Ca) 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 I_Ca density. Pretreatment with iodoresiniferatoxin, a specific transient receptor potential vanilloid type 1 (TRPV1) antagonist, or intracellular application of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid blocked the inhibitory effect of capsaicin on I_ca. However, neither W-7, a calmodulin blocker, nor KN-93, a CaMKII inhibitor, attenuated the inhibitory effect of capsaicin on I_Ca. 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 I_Ca. Interestingly, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, deltamethrin, cyclosporin A, and okadaic acid each alone significantly increased the I_Ca density and caused a depolarizing shift in the voltage dependence of activation. Immunofluorescence labeling revealed that capsaicin induced a rapid internalization of Ca_V2.2 channels on the membrane. Thus, this study provides novel information that VACCs are tonically modulated by the intracellular Ca²⁺ level and endogenous phosphatases in sensory neurons. Stimulation of TRPV1 by capsaicin down-regulates VACCs by dephosphorylation through Ca²⁺-dependent activation of calcineurin.

Received for publication, February 2, 2005 , and in revised form, March 2, 2005.

^* This work was supported by National Institutes of Health Grants GM64830 and NS45602. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Anesthesiology, H187, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA 17033. Tel.: 717-531-8433; Fax: 717-531-6221; E-mail: hpan{at}psu.edu.

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