Eur J Pharmacol 2014 Oct 05;740:35-44. doi: 10.1016/j.ejphar.2014.06.049.

Pregabalin activates ROMK1 channels via cAMP-dependent protein kinase and protein kinase C.

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Pregabalin (PGB) displays analgesic and anticonvulsant activities. Regulation of the resting membrane potential (RMP) by renal outer medullary potassium (ROMK1) channels may provide a mechanism for these activities. We examined the effects of PGB on ROMK1 channel activity. To investigate the regulatory effect of PGB on the activity of ROMK1 channel, we used inside-out excised membrane patches to measure the K+ current in Xenopus oocytes expressed either the wild-type (WT) or mutant ROMK1 channels. PGB concentration-dependently enhanced the activity of ROMK1 channels. PGB increases the WT channels, pHi gating residue mutant channels (K80M) and the mutant channels at phosphatidylinositol bisphosphate (PIP2)-binding sites (R188Q, R217A, and K218A). Our study suggests that PGB in the regulating of ROMK1 channel function are neither by pHi- nor PIP2-dependent mechanism. We found PGB failed to prompt the activity of consensus phosphorylation sites for protein kinase C (PKC) mutated channels (S183A, T191A, T193A, S201A and T234A). Furthermore, PGB did not stimulate the activity of channels in the presence of cAMP-dependent protein kinase (PKA) inhibitors, the mutants of the C-terminal PKA-phosphorylation sites (S219A and S313A), and the mutants constructed (S219D and S313D) which mimic the addition of negative charged associated with phosphorylation bound to a serine. These results demonstrated that PKA- and PKC-mediated phosphorylation represents a novel mechanism for PGB-activated ROMK1 channels. The enhancement of ROMK1 currents proves to an important molecular mechanism underlying the analgesic/anticonvulsant property of PGB for the restoration of RMP.

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Species referenced: Xenopus laevis
Genes referenced: camp kcnj1