Pharmacology & Physiology

Research Interests

 

Molecular determinants of the ionic regulatory differences between the cardiac and smooth muscle Na/Ca exchanger isoforms

 

The Na/Ca exchanger (NCX) expressed in the plasma membrane of almost every eukaryotic cell serves, in normal conditions, as a Ca 2+ extrusion mechanism driven by the Na + electrochemical gradient. However, Ca 2+ influx can occur through the exchanger in certain conditions. The NCX family consists of 3 genes: NCX1, NCX2 and NCX3. NCX1 is widely expressed while NCX2 and NCX3 are expressed in skeletal muscle and brain. NCX1 undergoes alternative splicing leading to several tissue-specific isoforms: NCX1.1 is the cardiac isoform, NCX1.3 is expressed in kidney and smooth muscle and NCX1.4 in brain.

In addition to being transported by the exchanger, Na + and Ca 2+ ions act as its allosteric regulators. Intracellular Na + induces an inactive conformation called Na-dependent inactivation I1, while the absence of cytosolic Ca 2+ induces the inactive state I2. We are interested in the functional differences in the regulatory properties of the NCX1 alternatively spliced isoforms NCX1.1 and NCX1.3 and their molecular determinants. Understanding these properties will contribute to our understanding of the contribution of NCX to pathological conditions like Ca 2+ overload in cardiac isquemia or Ca 2+ entry through NCX1.3 in arterial smooth muscle, possibly triggering salt-sensitive hypertension.