Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Pregabalin activates ROMK1 channels via cAMP-dependent protein kinase and protein kinase C. 2500 72

Although pregabalin has been shown to have preclinical and clinical efficacy in neuropathic pain, the mechanism of its antinociceptive action is still unknown in other pain states. This study aimed to evaluate the antinociceptive effect of pregabalin and its underlying spinal mechanisms related to mitogen activated protein kinases (MAPKs) in neuron and microglia following intraplantar injection of zymosan model. Zymosan evoked thermal hyperalgesia, mechanical hyperalgesia, and mechanical allodynia starting from 1 h and persistent until 5 h post-injection, which were dose-dependently reversed by oral pretreatment of pregabalin (3, 10, and 30 mg/kg). Pregabalin dramatically inhibited zymosan-induced Fos expression (a marker for neuronal activation) and microglia activation (using markers CD11b and ED1) in the spinal dorsal horn. Moreover, zymosan significantly increased phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 (double labeling with neuron), ERK5 (double labelling with neuron and microglia) and p38 MAPK (double labeling with microglia) in the spinal dorsal horn, which overall elevations were reversed by pregabalin. These findings suggest that blockage of MAPKs activation in neuron and microglia might be closely related to the antinociceptive effect of pregabalin on zymosan-induced peripheral inflammatory pain.
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PMID:Inhibition of mitogen-activated protein kinases phosphorylation plays an important role in the anti-nociceptive effect of pregabalin in zymosan-induced inflammatory pain model. 2509 29