Dynamic Regulation of Intracellular PH in the Heart

Abstract

Intracellular pH (pHi) is a key regulator of cellular functions. Cellular proteins rely on pHi to maintain their structures and functions. The mammalian heart beats incessantly with rhythmic mechanical activities generating acids that need to be buffered and removed from the cytosol to maintain a relatively stable pHi for normal cardiac function. Cardiac pHi is critical to cardiac excitation and contraction, and an uncompensated fall in pHi in cardiac ischemia impairs cardiac function and trigger arrhythmia and sudden cardiac death. It was reported that there exists spatial pHi non-uniformity in cardiomyocytes. However, it remains unknown how cardiac cells handle pHi on a beat-to-beat basis. We designed a method to measure simultaneous sarcomere contraction and pHi in cardiomyocytes. We found dynamic beat-to-beat acidification of pHi during a cardiac cycle, namely “pHi transients”. The pHi transients were coupled with cardiac contraction and regulated by pHi buffering capacity, pacing rate, HCO3-/Cl- transporters, and β-adrenergic signaling. Inhibition of the mitochondrial electron-transport chain significantly attenuates the pHi transients. Indeed, the dynamic changes in pHi during cardiac contraction reflects the rhythmic metabolic status in cardiomyocytes. Physiologically, the temporal pHi acidification may provide a beat-to-beat increase in the driving force for H+ transport to enhance mitochondrial ATP synthesis during cardiac contraction. Moreover, the beat-to-beat transient intracellular acidification may provide a negative feedback mechanism to cardiac contraction by facilitating relaxation due to the inhibitory effects on the contractile machinery by low pHi. Thus, in addition to dynamic electrical (action potentials), Ca2+ (Ca2+ transients), and mechanical regulatory systems (contractions), our study identified and demonstrated a new dynamic regulatory system (“pHi transients”) in the heart. Our results show that a cardiac cycle is sculpted not only by action potentials, Ca2+ transients, and contractions but also by cyclical changes in pHi.