Zebrafish as a Model System for the Study of Severe Ca2.1 (α) Channelopathies.

The P/Q-type Ca2.1 channel regulates neurotransmitter release at neuromuscular junctions (NMJ) and many central synapses. encodes the pore-containing α subunit of Ca2.1 channels. In humans, mutations result in a wide spectrum of neurological, neuromuscular, and movement disorders, such as familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), as well as a more recently discovered class of more severe disorders, which are characterized by ataxia, hypotonia, cerebellar atrophy, and cognitive/developmental delay. Heterologous expression of Ca2.1 channels has allowed for an understanding of the consequences of missense mutations on channel function. In contrast, a mechanistic understanding of how specific mutations lead to the resultant phenotypes is lacking. In this review, we present the zebrafish as a model to both study mechanisms of mutations that result in synaptic and behavioral defects and to screen for effective drug therapies to combat these and other Ca2.1 channelopathies.