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

• Published in: Biophysical journal Vol. 83; no. 1; pp. 5 - 21
• Main Authors: d’Alcantara, Pablo, Cardenas, Luz M., Swillens, Stéphane, Scroggs, Reese S.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.07.2002
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(02)75146-1

We previously demonstrated that activation of a 5HT4 receptor coupled cAMP-dependent signaling pathway increases tetrodotoxin-resistant Na+ current (INa) in a nociceptor-like subpopulation of rat dorsal root ganglion cells (type 2). In the present study we used electrophysiology experiments and computer modeling studies to explore the mechanism(s) underlying the increase of INa by 5HT. In electrophysiological experiments with type 2 dorsal root ganglion cells, 5HT increased peak INa and the activation and inactivation rate, without significantly affecting the voltage dependency of activation or availability. Studies on the voltage dependency of channel availability, time course of removal of inactivation, and inactivation of evoked Na+ currents suggested that there are at least two inactivation states of the Na+ channel, one (Ifast) that is induced and retrieved faster than the other (Islow). Long (1s), but not short (60 or 100ms), inactivating conditioning pulses (CPs) suppressed the 5HT-induced increase in INa. Computer modeling studies suggest that 5HT increased INa mainly by decreasing the transition rate (kOI1) from an open state to Ifast. Furthermore, 5HT increased INa activation and inactivation rates mainly by increasing the transition rate from closed to open (kC3O) and from Ifast to Islow (kI1I2), respectively. The antagonism of the 5HT-induced increase in INa by 1-s inactivation CPs may be due an enhancement of transitions from Ifast to Islow, via the increase in kI1I2. This may deplete the pool of channels residing in Ifast, reducing the frequency of reopenings from Ifast, which offsets the increase in INa produced by the reduction in kOI1. The above findings fit well with previous studies showing that activation of the cAMP/PKA cascade simultaneously increases voltage sensitive tetrodotoxin-resistant Na+ conductance and inactivation rate in nociceptors. The antagonism of the effects of 5HT by long inactivation CPs suggests that drugs designed to induce and/or stabilize the Islow state might be useful for reducing hyperalgesia produced by inflammatory mediators.