Résumé
The neuropeptide Endothelin-1 (Et-1), through the inositol triphosphate (IP3) pathway, is associated with a calcium release from the sarcoplasmic reticulum (SR). This RS depletion may open Store Operated Ca2+ Channel (SOCs) leading to an additional calcium influx. TRPM4 is a calciumactivated non-selective cationic channel ubiquitously expressed. It is involved in many physiological processes including the negative regulation of SOCs. However, its physiological role in cardiac level remains unclear. Our purpose was to determine whether TRPM4 channel is involved during excitation-contraction coupling (ECC) at atrial level where it's normally expressed and functional, in particular in response to the Et-1 during SOCs activation.
Atrial cardiomyocytes were isolated from 8 weeks-old wild-type C57bl/6J mice and ECC were analyzed by the Ionoptix® system with a myopacer and a Ca2+ fluorescent indicator (indo-1 AM). We used the 9-phenanthrol (10-5M) (9-Phe), as a selective inhibitor of the TRPM4 channel during cardiomyocytes stimulation with Et-1 (10-7M) to unmask TRPM4 function. With this approach, we demonstrated that i) as expected, Et-1 showed a positive inotropic effect on mouse atrial cardiomyocytes (sarcomere length shortening and calcium transient increased); ii) Et-1 effect was attenuated by 9-Phe application, showing an involvement of TRPM4 channel in the inotropic effect of Et-1 and iii) surprisingly the 9-Phe has an effect on calcium response without Et-1 application suggesting a role of TRPM4 channel in basal conditions.
This study has highlighted the involvement of TRPM4 channel in ECC of mouse atrial cardiomyocytes. In addition, Et-1 had a prohypertrophic effect, justifying the use of the Et-1 antagonists in humans. The TRPM4 channel, inhibited by 9-Phe, would be a possible new therapeutic target to prevent the pro-hypertrophic remodeling induced by Et-1.