My current research interest is focused on the study of Mg modulation of cardiac L-type Ca channel function. Intracellular Mg (Mgi) is altered in cardiovascular diseases associated with poor clinical outcome, and is a strong modulator of L-type Ca channels, a key determinant of cardiac excitability and Ca homeostasis.
Even though Mgi is the most abundant divalent ion in cells, relatively little is known about its homeostasis and physiological role. Mgi was shown to vary in different cardiovascular conditions such as transient ischemia, myocardial infarction and heart failure.
In ventricular myocytes, L-type Ca currents are conducted by Cav1.2 channels consisting of a pore-forming α1.2 subunit in association with β and α2δ subunits. The α1 subunits are composed of four homologous domains (I-IV) with each six transmembrane segments (S1-S6) and a re-entrant pore loop. Regulatory sites for Ca/calmodulin and c-AMP-dependent protein kinase are located in the C-terminal domain, which is also subject to in vivo proteolytic processing. The C-terminal domain contains an EF-hand motif that we showed to be involved in Mg mediated control of CaV1.2 amplitude and inactivation. A nearby IQ domain is directly implicated in Ca-dependent inactivation mediated by Ca/calmodulin.
Our overall goal is to determine the molecular mechanisms responsible for the modulatory actions of Mgi on L-type Ca channels and on the regulation by protein phosphorylation of these channels.
Our results will provide fundamental insights into the electrophysiological and molecular mechanisms of Mgi modulation of L-type Ca channels in cardiovascular health and disease conditions.
