Presynaptic calcium channels regulation by the ghrelin receptor (GHSR1a) activity

RAINGO J; LOPEZ SOTO JE; AGOSTI F; RODRÍGUEZ SS; PERELLO M

Buenos Aires

Conferencia; 5th Special Conference of the International Society for Neurochemistry, Synapses and Dendritic Spines in Health and Disease; 2012

International Society for Neurochemistry

Understanding the neural mechanisms underlying appetite control has became crucial for public health due to the world obesity pandemic. Currently, many pharmaceutical companies are developing strategies to inhibit central actions of ghrelin, the only peptide hormone known to increase food intake. Thus, a comprehensive understanding of ghrelin neurophysiological effects is necessary to design safe ghrelin- based clinical treatments. Ghrelin acts via the growth hormone secretagogue receptor type 1a (GHSR1a), a G protein coupled receptor that has an unusually high basal activity. In neurons, GHSR1a regulates gene expression, electric activity and neurosecretion. Here we tested whether basal and evoked activity of GHSR1a modifies presynaptic calcium channels activity as a mechanism to control neurotransmitter release. For this, we performed cell-attached patch-clamp recordings inHEK cells expressing GHSR1a and N-type calcium channels (CaV2.2). We found that the amount of GHSR cDNA plasmid used during the transfection inversely correlates with the percentage of transfected cells with detectable CaV2.2 basal current (slope =-88.5 l g1, r2=0.3,n=22 cells). Of note, the percentageoftransfectedcellswithdetectableCaV2.2 basal currents isnot affected by a mutated form of GHSR1a that lacks constitutive activity. Ghrelin treatment inhibits Ca V2.2 basal current levels in a concentration-dependent manner (16.0 ± 2.1 and 48.8 ± 3.3 % of total Ca V2.2 current for ghrelin 100 and 500 nM, respectively). This ghrelin-induced inhibition of Ca V2.2 current is partially washable and fully independent of the applied voltage. We thus conclude that basal and evoked GHSR1a activity inhibits presynaptic calcium channels and this effect could account for the physiological effect of ghrelin at presynaptic terminals. We are currently investigating the pathways mediating this effect and the modulation of these pathways by newly synthesized agonist and antagonist of GHSR1a. Supported by PICT2010?1589 and PICT2010?1954