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J Physiol Volume 583, Number 1, 175-193, August 15, 2007 DOI: 10.1113/jphysiol.2007.133231
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NEUROSCIENCE

Transient receptor potential TRPA1 channel desensitization in sensory neurons is agonist dependent and regulated by TRPV1-directed internalization

 Armen N. Akopian1, Nikita B. Ruparel2, Nathaniel A. Jeske1 and Kenneth M. Hargreaves1,3

Departments of
1 Endodontics
2 Cellular and Structural Biology
3 Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

The pharmacological desensitization of receptors is a fundamental mechanism for regulating the activity of neuronal systems. The TRPA1 channel plays a key role in the processing of noxious information and can undergo functional desensitization by unknown mechanisms. Here we show that TRPA1 is desensitized by homologous (mustard oil; a TRPA1 agonist) and heterologous (capsaicin; a TRPV1 agonist) agonists via Ca2+-independent and Ca2+-dependent pathways, respectively, in sensory neurons. The pharmacological desensitization of TRPA1 by capsaicin and mustard oil is not influenced by activation of protein phosphatase 2B. However, it is regulated by phosphatidylinositol-4,5-bisphosphate depletion after capsaicin, but not mustard oil, application. Using a biosensor, we establish that capsaicin, unlike mustard oil, consistently activates phospholipase C in sensory neurons. We next demonstrate that TRPA1 desensitization is regulated by TRPV1, and it appears that mustard oil-induced TRPA1 internalization is prevented by coexpression with TRPV1 in a heterologous expression system and in sensory neurons. In conclusion, we propose novel mechanisms whereby TRPA1 activity undergoes pharmacological desensitization through multiple cellular pathways that are agonist dependent and modulated by TRPV1.

(Received 22 March 2007; accepted after revision 15 June 2007; first published online 21 June 2007)
Corresponding author: A. N. Akopian, University of Texas Health Science Center @ San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. Email: akopian{at}uthscsa.edu

This paper has online supplemental material.




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