The KLHL1 KO as a Model of Altered T-Type Ca Channel Function

PERISSINOTTI, PP; MARTÍNEZ-HERNÁNDEZ, ELIZABETH; ETHINGTON EG; ALMAZAN, ERIK; ZEGLIN, ALISSA; KOOB, MICHAEL D.; PIEDRAS-RENTERÍA, ERIKA S.

MASSACHUSETTS

Congreso; THE SEVENTIETH ANNUAL MEETING OF THE SOCIETY OF GENERAL PHYSIOLOGISTS: Genetic and Animal Models for Ion Channel Function in Physiology and Disease; 2016

SOCIETY OF GENERAL PHYSIOLOGISTS 71st ANNUAL SYMPOSIUM

The physiological consequences of the global deletion of the Kelch-like 1 protein (KLHL1) in mice willbe discussed. KLHL1 is a neuronal actin-bindingprotein that modulates CaV2.1 P/Q-type and CaV3.2T-type channel activity. Decreased expression andfunction of these two channel types is seen when KLHL1is acutely down-regulated using specifi c shRNA; however, the KLHL1 KO mouse displays tissue-specifi c Cacurrent homeostasis that can result in normal, decreased, or increased Ca currents. Altered Ca channelfunction and Ca current levels, neuronal excitabilitychanges, and synaptic function are detected in thismodel.Here, we will discuss our most recent fi ndings on theKLHL1 KO mouse as a model to assess altered T-typechannel expression. The hypothalamus from KO miceexhibits slightly decreased CaV3.2 expression as expected for this model, however CaV3.1 levels are highlyup-regulated, resulting in increased LVA channel activity, increased excitability of pro-opiomelanocortin?positive neurons, and T type channel-mediated resistance tothe satiety hormone leptin, as well as abnormal responsesafter a 20-h period of food deprivation. In contrast, KOdorsal root ganglia display decreased LVA CaV3.2 expression without additional compensations, resultingin decreased LVA currents, decreased DRG excitability, and increased threshold to mechanical pain. Insummary, the KLHL1 KO mouse model is an excellent system to explore how moderate Ca channel function changes affect neuronal tissues. Our results alsoestablish T-type channels as possible targets for obesitytreatment.Supported by NSF grant no. 1022075 and CONACyTMéxico grant no. 203082.