Role of Protons in Calcium Signaling

Abstract

36 years after the publication of the important article by Busa and Nuccitelli on the variability of intracellular pH (pHi) and the interdependence of pHi and intracellular Ca2+ concentration ([Ca2+]i), little research has been carried out on pHi and calcium signaling. Moreover, the results appear to be contradictory. Some authors claim that the increase in [Ca2+]i is due to a reduction in pHi, others that it is caused by an increase in pHi. The reasons for these conflicting results have not yet been discussed and clarified in an exhaustive manner. Variations in pHi have a significant impact on the increase in [Ca2+]i and hence on some of the basic biochemical mechanisms of calcium signaling. This paper focuses on the possible triggering role of protons, highlighting the mechanisms potentially involved and the open issues that could be clarified by research.

Environmental and Endogenous Acids Can Trigger Allergic-Type Airway Reactions

“…The hydrolysis of phospholipid esters and the generation of endogenous acid molecules, such as arachidonic acid (AA), phosphatidic acid, and IP 3 , are at the base of the production of allergic mediators. It is known that external acidification can cause mobilization of the segregated Ca 2+ from intracellular stores [ 38 , 39 , 46 , 47 , 53 , 55 , 56 , 57 , 58 , 59 ], because protons can readily replace Ca 2+ in its ligand locations [ 53 , 60 , 61 , 62 ]. Moreover, it is known that the increase of [Ca 2+ ] c is involved in many physiological processes [ 63 , 64 , 65 , 66 , 67 ], but also in the triggering of pathological manifestations such as allergic responses [ 65 ], airway hyper-responsiveness (AHR) [ 66 ], and abnormal contraction and remodeling of airway smooth muscle (ASM) [ 67 ].…”

“…Contact between the agonist and the receptor triggers a PLC/IP 3 -pathway-type complex chain reaction which, via the activation of numerous enzymes and the increase in the concentration of H + and cytosolic Ca 2+ (respectively (H + ) c and (Ca 2+ ) c ), culminates with degranulation, by the exocytotic secretion of allergic mediators and the onset of an acute allergic response. The responses of the various agonist/receptor couples may differ [ 69 , 77 , 84 ], but depend in each case on the concentration and affinity of the agonist [ 74 ], and the fundamental steps in the basic biochemical mechanism of allergic reactions do not vary ( Figure 1 ): The stimulation of the receptor, both of the FcεRI and GPCR types, activates phospholipase C (PLC) [ 85 , 86 , 87 , 88 ] and hence the hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP 2 ) on the inner wall of the plasma membrane, generating and releasing IP 3 , a protonated acid salt [ 62 , 89 ], in the cytosol; Through dissociation, the IP 3 releases H + [ 62 , 89 ] and, via its IP 3 R receptor, induces cell calcium release and store depletion, increasing (Ca 2+ ) c [ 62 , 90 ]; The increase in (Ca 2+ ) c activates numerous calcium-dependent enzymes, including phospholipase A 2 (PLA 2 ), which produces arachidonic acid (AA) [ 91 , 92 ], which in turn dissociates releasing more H + and inducing the release of more Ca 2+ [ 56 , 58 , 93 ]; from the AA hundreds of derivatives (eicosanoids cascade) are formed, including leukotrienes (LTs) and prostaglandins (PGs) [ 94 , 95 ]. Both leukotrienes and prostaglandins are known to play a pivotal role in inflammatory and allergic reactions; The store depletion stimulates the entry of more Ca 2+ from the extracellular space (calcium influx) via the mechanism known as Store Operated Calcium Entry (SOCE), in which, from the surface of the Endoplasmic Reticulum (ER), Stromal Interaction Molecule1 (STIM1) activates the opening of ORAI1 and Transient Receptor Potential Cation Canonical (TRPC) [ …”

“…The stimulation of the receptor, both of the FcεRI and GPCR types, activates phospholipase C (PLC) [ 85 , 86 , 87 , 88 ] and hence the hydrolysis of phosphatidylinositol 4,5-biphosphate (PIP 2 ) on the inner wall of the plasma membrane, generating and releasing IP 3 , a protonated acid salt [ 62 , 89 ], in the cytosol;…”

“…Through dissociation, the IP 3 releases H + [ 62 , 89 ] and, via its IP 3 R receptor, induces cell calcium release and store depletion, increasing (Ca 2+ ) c [ 62 , 90 ];…”

“…Figure 1 shows two different steps in the intracellular generation of H + through the action of phospholipase, the first dependent on the IP 3 produced by PLC, the second on the AA produced by PLA 2 . A third step, not shown in Figure 1 , can depend on the action of phosphatases which dephosphorilate the IP 3 on IP 3 R [ 62 ]. Each of these three steps gives rise to a rapid transient increase in (H + ) c .…”