Activation of peripheral KCNQ channels relieves gout pain.
Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels. In cultured recombinant cells, BBR exhibited significant potentiation effects on KCNQ channels comparable to previously reported classical activators. In native dorsal root ganglion neurons, BBR effectively overcame the suppression of KCNQ currents, and the resultant neuronal hyperexcitability caused by inflammatory mediators, such as bradykinin (BK). Benzbromarone consistently attenuates BK-, formalin-, or monosodium urate-induced inflammatory pain in rat and mouse models. Notably, the analgesic effects of BBR are largely mediated through peripheral and not through central KCNQ channels, an observation supported both by pharmacokinetic studies and in vivo experiments. Moreover, multiple residues in the superficial part of the voltage sensing domain of KCNQ channels were identified critical for the potentiation activity of BBR by a molecular determinant investigation. Our data indicate that activation of peripheral KCNQ channels mediates the pain relief effects of BBR, potentially providing a new strategy for the development of more effective therapies for gout.
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Yueming
Y
Zheng
Haiyan
H
Xu
Li
L
Zhan
Xindi
X
Zhou
Xueqin
X
Chen
Zhaobing
Z
Gao
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D001553:Benzbromarone / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004195:Disease Models, Animal; D005557:Formaldehyde / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology; D006624:Hippocampus / Q000166:cytology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000633:toxicity; D014528:Uricosuric Agents / Q000494:pharmacology / Q000627:therapeutic use
D051658:KCNQ2 Potassium Channel; D014528:Uricosuric Agents; D005557:Formaldehyde; D014527:Uric Acid; D001553:Benzbromarone