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J. Biol. Chem., Vol. 280, Issue 50, 41683-41693, December 16, 2005

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Tyrosine Phosphorylation of K_ir3.1 in Spinal Cord Is Induced by Acute Inflammation, Chronic Neuropathic Pain, and Behavioral Stress^*

Danielle L. Ippolito12, Mei Xu1, Michael R. Bruchas, Kevin Wickman, and Charles Chavkin3

From the Department of Pharmacology, University of Washington, Seattle, Washington 98195 and the Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

Tyrosine phosphorylation is an important means of regulating ion channel function. Our previous gene expression studies using the Xenopus laevis oocyte system suggested that tyrosine phosphorylation of G-protein-gated inwardly rectifying potassium channels (K_ir3 or GIRK) suppressed basal channel conductance and accelerated channel deactivation. To assess whether similar mechanisms regulate K_ir3 function in mammalian cells, we developed and characterized a phosphoselective antibody recognizing K_ir3.1 phosphorylated at tyrosine 12 in the N-terminal domain and then probed for evidence of K_ir3.1 phosphorylation in cultured mammalian cells and spinal cord. The antibody was found to discriminate between the phospho-Tyr¹² of K_ir3.1 and the native state in transfected cell lines and in primary cultures of mouse atria. Following either mouse hindpaw formalin injection or sciatic nerve ligation, pY12-K_ir3.1 immunoreactivity was enhanced unilaterally in the superficial layers of the spinal cord dorsal horn, regions previously described as expressing K_ir3.1 channels. Mice lacking K 3.1 following targeted gene disruption did not show specific pY12-K_ir3.1 immunoreactivity after sciatic nerve ligation. Further, mice exposed to repeatedly forced swim stress showed bilateral enhancement in pY12-K_ir3.1 in the dorsal horn. This study provides evidence that K_ir3 tyrosine phosphorylation occurred during acute and chronic inflammatory pain and under behavioral stress. The reduction in K_ir3 channel activity is predicted to enhance neuronal excitability under physiologically relevant conditions and may mediate a component of the adaptive physiological response.

Received for publication, June 29, 2005 , and in revised form, September 19, 2005.

^* This work was supported by the United States Public Health Service Grant DA11672 from NIDA, National Institutes of Health and National Institutes of Health Grants MH61933 and DA11806. 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.

¹ Both authors contributed equally to this work.

² Supported in part by Training Grant PHS NRSA T32 GM07270 from the National Institutes of Health.

³ To whom correspondence should be addressed: Dept. of Pharmacology, University of Washington, Box 357280, 1959 Pacific Ave. N. E., Seattle, WA 98195-7280. Tel.: 206-543-4266; Fax: 206-685-3822; E-mail: cchavkin{at}u.washington.edu.

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