The Brugada syndrome mutation A39V does not affect surface expression of neuronal rat Cav1.2 channels

We report that despite the striking loss of trafficking described previously in the cardiac Cav1.2 channel, the A39V mutation while in the background of the brain isoform traffics and functions normally. We detected no differences in biophysical properties between wild type Cav1.2 and A39V-Cav1.2 in the presence of either a cardiac (Cavβ2b), or a neuronal beta subunit (Cavβ1b). In addition, the A39V-Cav1.2 mutant showed a normal Cavβ2b mediated increase in surface expression in tsA-201 cells.The Brugada syndrome mutation A39V when introduced into rat brain Cav1.2 does not trigger the loss-of-trafficking phenotype seen in a previous study on the human heart isoform of the channel.Cav1.2 is an L-type voltage-gated calcium channel that is indispensible for proper function of organs including the brain and the heart [1]. Structurally, Cav1.2 channel complexes are composed of a pore-forming Cavα1 subunit, an accessory Cavα2δ subunit, and a Cavβ trafficking chaperone [2] which interacts with the Cavα1 subunit at the intracellular region linking the first two transmembrane domains [3-5]. Extensive alternate splicing of Cav1.2 between neuronal and cardiac backgrounds alters channel structure and function, as does the type of Cavβ subunit that is expressed in a given tissue [6-9]. Gain of function mutations in Cav1.2 channels may result in a multi-organ disease known as Timothy syndrome which is characterized by cardiac symptoms such as a prolonged Q-T interval, arrhythmias and sudden cardiac death (SCD); as well as immune dysfunction and autism [10]. A loss of Cav1.2 function on the other hand, can give rise to a heart specific disorder termed Brugada syndrome whose phenotype consists of a shortened Q-T interval, ventricular fibrillation and SCD [10]. Brugada syndrome has been associated with a gain of function in KCNE potassium channels [11], as well as a loss of function of Nav1.5 (15% of all cases) and Cav1.2/Cavβ (5% of all cases) [1,12]. How exactly increased Cav1.2 ac