Figure 6. TBX5 and GATA4 are key regulators of atrial calcium homeostasis.

Proteins involved in Ca²⁺ handling of atrial myocytes. In the healthy atrium, calcium homeostasis is maintained through a tight balance between Ca²⁺ fluxes across the membrane. Reducing Tbx5 gene dosage in the adult heart results in depressed Atp2a2 expression and SERCA2 function, affecting SR Ca²⁺ influx. Abnormal Ca²⁺ handling leads to Ca²⁺ accumulation in the cytosol, contributing to ectopic atrial activity, prolonged APs, and atrial arrhythmias observed with adult-specific Tbx5 haploinsufficiency. Reducing Gata4 gene dosage rescues Atp2a2 expression, SERCA2 function and SR Ca²⁺ uptake, restoring sinus rhythm. SERCA2 and its inhibitory protein PLN play a fundamental role in Ca²⁺ handling within atrial myocytes. Reducing Pln gene dosage, as a means to modulate SERCA2 function, normalizes SERCA2 activity and SR Ca²⁺ uptake, resulting in restoration of sinus rhythm in combined Tbx5/Pln haploinsufficiency.