Pathophysiology of the late sodium current: from myocardium to pancreatic beta cells

The sustained component of the sodium current (INaL) has been recently found enhanced in several cardiac pathologies. INaL enhancement has been highlighted as a major cause of cellular dysfunction, caused by INaL-dependent electrical instability (arrythmias) and alterations in intracellular ions (Na and Ca) homeostasis. Recent evidence of beneficial effects of the INaL blocker ranolazine (RAN) in diabetes motivates interest in the role of the INaL in glucose-induced insulin secretion (GSIS). The aim of the present thesis is to characterize INaL, identified as steady-state current blocked by RAN (IRAN) or TTX (ITTX), and its function in rat INS-1E cells and human islet cells (HIc). Veratridine (VERA) was used as INaL enhancer. Baseline INaL was similar between INS-1E and HIc. In INS-1E cells, tolbutamide-triggered action potentials were suppressed by TTX, but not by RAN. VERA caused depolarization, countered by INaL blockade. ITTX and IRAN reversal potentials (EREV) were negative to Na+ equilibrium one, but they approached it when K+-channels were blocked. This revealed INaL coupling to Na+-activated K+ current (IKNa); expression of IKNa channels (Slo2.1/2.2) was confirmed by transcript analysis. Concomitant activation of IKNa might blunt the effects of INaL on membrane potential, but at the same time it might increase the impact of INaL on intracellular Ca2+. Consistently, INaL blockade (by TTX) blunted cytosolic Ca2+ response to depolarization, with the highest effect in the intermediate potentials. Long-term exposure to 33 mM glucose (CHG) enhanced INaL. Whereas acute INaL enhancement (VERA) increased GSIS, chronic one (CHG or VERA) depressed GSIS, which was partially restored by RAN. Conclusions: 1) INaL is expressed in insulin-secreting cells, is coupled to IKNa, affects Ca2+ signalling and, when enhanced acutely, increases GSIS 2) sustained hyperglycemic stress enhances INaL and this contributes to GSIS depression instead. Overall, INaL enhancement may represent a common mechanism contributing to disease progression in cardiac and secretion disorders.