title: A novel mechanism of modulation of 5-HT₃A receptors by hydrocortisone.
abstract: Modulation of Cys-loop receptors by steroids is of physiological and therapeutical relevance. Nonetheless, its molecular mechanism has not been elucidated for serotonin (5-HT) type 3 receptors. We deciphered the mechanism of action of hydrocortisone (HC) at 5-HT type 3A receptors. Single-channel currents from the high-conductance form (∼4.7 pA, -70 mV) appear as a series of long opening events forming bursts, which group into long clusters. Although they are very infrequent, subconductance events (∼2.4 pA) are detected within clusters. HC produces a significant concentration-dependent reduction in open and burst durations, demonstrating open-channel block. In addition, it increases the appearance of subconductance levels in a concentration- and slightly voltage-dependent manner. The amplitude of the subconductance level does not change with HC concentration and its open duration is briefer than that of full amplitude events, indicating lower open-channel stability. Dual effects are distinguished from macroscopic responses: HC reduces amplitude by acting from either open or closed states, and it increases decay rates from the open state. Thus, HC acts as a negative modulator of 5-HT type 3A receptors by different mechanisms: It acts as an open-channel blocker and it favors opening to a preexisting subconductance level. The latter constitutes a novel, to our knowledge, mechanism of channel modulation, which might be applicable to other steroids and channels.
authors.affiliation: Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur-CONICET, Bahía Blanca, Argentina.
authors.forename: Jeremías
authors.initials: J
authors.lastname: Corradi
authors.forename: Natalia
authors.initials: N
authors.lastname: Andersen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bouzat
mesh_terms: D000818:Animals; D006854:Hydrocortisone / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D044406:Receptors, Serotonin, 5-HT3; D006854:Hydrocortisone