Worm migraines: Characterization of gain-of-function mutation in the voltage-gated calcium channel, UNC-2/CaV2 2

RAYES, D.H.; HUANG, Y.-C.; PIRRI, J.; SAHEKI, Y.; BARGMANN, C.; FRANCIS, M.; ALKEMA, M.

Huerta Grande

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2013

Fusion of synaptic vesicles with the cell membrane is initiated by the activation of presynaptic voltage-gated Ca++ channels (CaV2). C. elegans has a single presynaptic CaV2α subunit, UNC-2. We identified an unc-2 gain-of-function (gf) mutant, which displays hyperactive locomotion. Animals that express the unc-2(gf) in the backward locomotion interneurons exhibit an increased reversal frequency, while expression in the hermaphrodite specific neurons produces hyperactive egg-laying, suggesting that the unc-2(gf) transgene can be used to hyper-activate selective neurons. unc-2(gf) mutants show an increased frequency of endogenous synaptic release events, indicating elevated levels of neurotransmitter release. Whole-cell recordings from HEK cells expressing the human CaV2.1α with the corresponding unc-2(gf) mutation revealed activation at lower membrane potentials. Our findings are similar to those reported for some mutations in the human CaV2.1α that cause Familial Hemiplegic Migraine (FHM1). Interestingly, animals that express unc-2 carrying corresponding FHM1 mutations display a phenotype similar to that of the unc-2(gf) mutants. Therefore, the unc-2(gf) mutants may provide an invertebrate model to study mechanisms underlying FHM1. To understand mechanisms of CaV2 function in vivo, we performed a screen for mutants that suppress the hyperactive phenotype of unc-2(gf) mutants. This suppressor screen may provide novel targets for the treatments of Ca++ channelopathies.