Role of inositol 1,4,5-trisphosphate receptor type 1 in ATP-induced nuclear Ca2+ signal and hypertrophy in atrial myocytes

Highlights: • IP₃ receptor type 1 (IP₃R1) are expressed in atrial cell perinucleus. • IP₃R1 mediates ATP-induced sustained nuclear Ca²⁺ increase in HL-1 atrial cells. • IP₃R1 contributes to higher sensitivity of nuclear release sites upon IP₃ increase. • Larger Ca²⁺ content in perinuclear store of atrial cells involves IP₃R1. • IP₃R1 signaling may play a role in ATP-induced atrial cell hypertrophy. Inositol 1,4,5-trisphosphate receptor type 1 (IP₃R1) is expressed in atrial muscle, but not in ventricle, and they are abundant in the perinucleus. We investigated the role of IP₃R1 in the regulations of local Ca²⁺ signal and cell size in HL-1 atrial myocytes under stimulation by IP₃-generating chemical messenger, ATP. Assessment of nuclear and cytosolic Ca²⁺ signal using confocal Ca²⁺ imaging revealed that IP₃ generation by ATP (1 mM) induced monophasic nuclear Ca²⁺ increase, followed by cytosolic Ca²⁺ oscillation. Genetic knock-down (KD) of IP₃R1 eliminated the monophasic nuclear Ca²⁺ signal and slowed the cytosolic Ca²⁺ oscillation upon ATP exposure. Prolonged application of ATP as well as other known hypertrophic agonists (endothelin-1 and phenylephrine) increased cell size in wild-type cells, but not in IP₃R1 KD cells. Our data indicate that IP₃R1 mediates sustained elevation in nuclear Ca²⁺ level and facilitates cytosolic Ca²⁺ oscillation upon external ATP increase, and further suggests possible role of nuclear IP₃R1 in atrial hypertrophy.