Multiple H+ sensors mediate the extracellular acidification-induced [Ca2+]i elevation in cultured rat ventricular cardiomyocytes

Abstract

Acidosis has been known to cause “Ca2+ transients”, however, the mechanism is still uncertain. Here, we demonstrated that multiple H+ sensors, such as ASICs, TRPV1 and proton-sensing G protein coupled receptors (GPCRs) are involved in extracellular acidification-induced intracellular calcium ([Ca2+]i) elevation. By using calcium imaging measures, we observed that both ASIC and TRPV1 channels inhibitors suppressed the [Ca2+]i elevation induced by extracellular acidosis in cultured rat cardiac myocytes. Then, both channels mRNA and proteins were identified by RT-PCR, western blotting and immunofluorescence. ASIC-like and TRPV1-like currents were induced by extracellular acidification, suggesting that functional ASIC and TRPV1 channels jointly mediated extracellular calcium entry. Furthermore, either pre-exhaustion of sarcoplasmic reticulum (SR) Ca2+ with thapsigargin or IP3 receptor blocker 2-APB or PLC inhibitor U73122 significantly attenuated the elevation of [Ca2+]i, indicating that the intracellular Ca2+ stores and the PLC-IP3 signaling also contributed to the acidosis-induced elevation of [Ca2+]i. By using genetic and pharmacological approaches, we identified that ovarian cancer G protein-coupled receptor 1 (OGR1) might be another main component in acidosis-induced release of [Ca2+]i. These results suggest that multiple H+-sensitive receptors are involved in “Ca2+ transients” induced by acidosis in the heart.

Cardiac vanilloid receptor-1 afferent depletion enhances stellate ganglion neuronal activity and efferent sympathetic response to cardiac stress

“…TRPV1 expression in cardiomyocytes has been reported; however, its location and function in myocytes remain highly controversial. It has been reported to be in the cytosol, cell membrane, and mitochondrial membrane in different studies (5,15,17). Given this controversy, it is not clear whether the stress responses in our study were affected.…”

Acid‐sensing ion channel 1a is involved in ischaemia/reperfusion induced kidney injury by increasing renal epithelia cell apoptosis

“…Accumulating evidence demonstrated that ASICs participate in pathological progress of various organs such as brain, retinal, heart and articular cartilage ischaemic injuries. [17][18][19][20] ASIC1a a Ca 2+ -permeable ASICs subunit serve as novel targets for ischaemic stroke therapy. 8…”

Acids Can Promote the Onset and Multimorbidity of Allergic and Nonallergic Airway Diseases

“…Regarding endogenous acids, it should be remembered that cells use intracellular enzymes such as phospholipase C (PLC) and messengers such as inositol 1,4,5-trisphosphate (IP3) to increase the free Ca 2+ concentration in cytosol ([Ca 2+ ]c). PLC and other phospholipases are powerful acidifying enzymes, because one H + is released for each hydrolysed ester bond [47][48][49] . The hydrolysis of phospholipid esters and the generation of endogenous acids, such as arachidonic acid (AA), phosphatidic acid, and IP3, are at the base of the production of allergic mediators.…”

“…The hydrolysis of phospholipid esters and the generation of endogenous acids, such as arachidonic acid (AA), phosphatidic acid, and IP3, are at the base of the production of allergic mediators. It is known that acidification can cause mobilization of the segregated Ca 2+ from intracellular stores 33,34,41,42,[50][51][52][53][54] , because protons can readily replace Ca 2+ in its ligand locations 48,55,56 . Moreover, it is known that the increase of [Ca 2+ ]c is involved in many physiological processes [57][58][59][60][61] but also in the triggering of pathological manifestations such as allergic responses 59 , airway hyper-responsiveness (AHR) 60 , and abnormal contraction and remodelling of airway smooth muscle (ASM) 61 .…”

“…Given the sheer number of GPCRs, many combinations with different agonists are possible. For example, GPR4, GPR65, GPR68 and GPR132 receptors may be activated by extracellular protons 43,44,48,75,76 . Alternatively, muscarinic agonists may stimulate the Gαq/11 subunits of the acetylcholine GPCRs 43 .…”