Reduced Transition between Open and Inactivated Channel States Underlies 5HT Increased INa+ in Rat Nociceptors

摘要: We previously demonstrated that activation of a 5HT(4) receptor coupled cAMP-dependent signaling pathway increases tetrodotoxin-resistant Na(+) current (I(Na)) in nociceptor-like subpopulation rat dorsal root ganglion cells (type 2). In the present study we used electrophysiology experiments and computer modeling studies to explore mechanism(s) underlying increase I(Na) by 5HT. electrophysiological with type 2 cells, 5HT increased peak inactivation rate, without significantly affecting voltage dependency or availability. Studies on channel availability, time course removal inactivation, evoked currents suggested there are at least two states channel, one (I(fast)) is induced retrieved faster than other (I(slow)). Long (1 s), but not short (60 100 ms), inactivating conditioning pulses (CPs) suppressed 5HT-induced I(Na). Computer suggest mainly decreasing transition rate (k(OI1)) from an open state I(fast). Furthermore, rates increasing closed (k(C3O)) I(fast) I(slow) (k(I1I2)), respectively. The antagonism 1-s CPs may be due enhancement transitions I(slow), via k(I1I2). This deplete pool channels residing I(fast), reducing frequency reopenings which offsets produced reduction k(OI1). above findings fit well previous showing cAMP/PKA cascade simultaneously sensitive conductance nociceptors. effects long suggests drugs designed induce and/or stabilize might useful for hyperalgesia inflammatory mediators.