Does voltage-gated calcium channels (CaV) activity inhibition by constitutive growth hormone secretagogue receptor type 1a (GHSR1a) activity depend on CaVβ auxiliary subunit?

MUSTAFÁ ER; LÓPEZ SOTO EJ; QUELAS,JUAN IGNACIO; MARTÍNEZ DAMONTE V; RODRÍGUEZ SS; RAINGO J

Mar del Plata

Congreso; XXX CONGRESO ANUAL DE LA SAN; 2015

Sociendad Argentina de investigaciones en Neurociencias

GHSR1a is the receptor of ghrelin, which participates in neural circuits involved in physiological functions such as food intake, stress and memory. One of its main features is its constitutive activity (CA) that seems to be relevant due to its expression in brain areas with restricted access to ghrelin. We have shown that GHSR1a CA impairs presynaptic CaV (CaV2.1 and CaV2.2) activity by reducing their surface expression. We are now investigating which structures of CaV are the targets of GHSR1a CA. We found that GHSR1a CA also inhibits other channels with different pore-forming subunits: the high voltage activated (HVA) CaV, CaV1.2 and CaV1.3, but not a low voltage activated (LVA) CaV: CaV3.2. All the HVA CaV tested have in common that CaVβ auxiliary subunit modulates their surface expression, degradation and gating, so we included CaVβ in such experiments, while we did not when we tested the LVA CaV, which was not affected by GHSR1a CA. Thus, we hypothesize that CaVβ may be the target of GHSR1a CA. We found that GHSR1a is able of inhibiting all CaV subtypes only when CaVβ is included in the channel complex, while the presence of CaVα2δ auxiliary subunit is not required. We are currently testing several mutated CaVβ at key aminoacids that could be targeted by protein kinases activated by GHSR1a CA. Our results point to a new function of CaVβ auxiliary subunit as a joint factor that controls CaV trafficking and the impact of G protein-coupled receptors activity on CaV.