A Novel Mechanism of Modulation of 5-HT3A receptors by Hydrocortisone

JEREMÍAS CORRADI; NATALIA ANDERSEN; CECILIA BOUZAT

Huerta Grande, Córdoba

Congreso; II Reunión Conjunta de Neurociencias; 2010

Sociedad Argentina de Neurociencias

Modulation of Cys-loop receptors by steroids is of physiological and therapeutical relevance. Nonetheless, its molecular mechanism has not been elucidated for 5-HT3 receptors. We deciphered the mechanism of action of hydrocortisone (HC) at 5-HT3ARs. Single-channel currents from the high conductance form triggered by 1 mM 5-HT appear as a series of long opening events of ~4.7 pA (-70 mV) forming bursts, which group into long clusters. Though very infrequently (relative area <0.1), subconductance events (~2.4 pA) are detected within clusters. HC produces a significant concentration-dependent reduction in open and burst durations, from ~110 ms and ~800 ms in the absence of steroid, to ~3 ms and ~25 ms in the presence of 400 mM HC, respectively. These results support an open-channel blockade. In addition, it increases in a concentration- and slightly voltage-dependent manner the appearance of subconductance levels. The amplitude of the subconductance level does not change with HC concentration and its open duration is briefer than that of full amplitude events (0.3±0.1 ms), indicating lower open-channel stability. Dual effects are distinguished from macroscopic responses: HC reduces amplitude (~50% at 400 µM HC) by acting from both open or closed states, and increases decay rates from the open state. Thus, HC acts as a negative modulator of 5-HT3AR by different mechanisms: It acts as an open-channel blocker and it favors opening to a pre-existing subconductance level. The latter constitutes a novel mechanism of channel modulation, which might be applicable to other steroids and channels