Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

15-POS Board 15 Minocycline Inhibits ASIC Currents in Dorsal Root Ganglion Neurons by a Selective Action on the ASIC1a Channel Subunit Caba Sánchez Laura Cecilia 1 , Soto Eguibar Enrique 1 , Vega Y Saenz de Miera Maria del Rosario 1 , Félix Grijalva Ricardo 2 . 1 Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla, Puebla, México. 2 Departamento de Biología Celular, Centro de Investigación y Estudios Avanzado del Instituto Politécnico Nacional (CINVESTAV-IPN), CDMX, México Acid Sensing Ion Channels (ASIC) are proton-activated Na+ channels expressed in the nervous system, where they are involved in learning, fear behavior, neurodegeneration, nociception, mechanoreception, chemoreception, ischemia, epilepsy, inflammation, among others. Thus, the discovery of pharmacological agents targeting ASICs has high therapeutic potential. Minocycline is a semisynthetic antibiotic of the tetracycline family that has neuroprotective properties, in processes in which ASICs have been involved (such as neurodegeneration, nociception, and inflammation), which led us to postulate the ASICs as a minocycline target. As we hypothesized, whole cell voltage clamp recordings from isolated dorsal root ganglion (DRG) neurons from the rat, shown that minocycline inhibits the peak amplitude of proton gated current (ASIC) neurons in a dose-dependent manner (IC50 ~ 100 μM). In heterologous expression system CHO-cells, minocycline selectively inhibits the ASIC1a currents without significant inhibitory effects in ASIC2a, ASIC1b or ASIC3 currents. Molecular anchor analysis (in-silico analyses) suggests the “acid pocket” and the “central vestibule” as putative minocycline bindings sites in the chicken ASIC1a channel. These results demonstrate the inhibitory action of minocycline on the ASIC currents, contributing to account for the neuroprotective action of minocycline, and opening a venue for research of tetracycline derived molecules as potentially relevant drugs to manipulate ASIC currents, and to improve neuroprotective therapeutic armamentarium.

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