Protons are present in virtually all aqueous solutions. Even more, protons are produced by cellular metabolism and their concentration may be further influenced by the partial pressure of CO2 inside or outside of cells. Thus, uni- and multicellular organisms are faced with the intra- and/or extracellular presence of protons, and their concentration may change according to environmental conditions, diet, cellular metabolism, organ function, and possibly disease. Protons are not only end or byproducts of metabolic processes, but they are powerful chemical modifiers of biological processes and have more recently emerged as signaling molecules.

Protons modify a myriad of biological processes as changes in pH cause protonation or deprotonation of various amino acid residues or modify surface charges of molecules thereby altering enzyme kinetics, ion channel activity, receptor-ligand interactions, or local ion concentrations, just to name a few consequences. Many of these processes have a very steep pH dependence as evident from individuals with seemingly small deviations of systemic pH that cause acidosis or alkalosis. These states are defined as deviations of normal blood pH outside the range of pH 7.36–7.44 indicating how tightly systemic pH is regulated. It takes only minor deviations from this normal pH range, 0.1–0.2 pH units, to cause complex clinical syndromes. Acute or chronic acidosis or alkalosis cause not only compensatory reactions in kidney and respiratory functions but also alter blood flow and pressure, cause shifts in electrolytes, affect bone, alter hormone concentrations and signaling, alter muscle and liver metabolism, and affect various brain functions. During evolution, a complex regulatory system to sense, control, and regulate pH has evolved to maintain a stable environment for our cells and organs. Many of the mechanisms to control systemic pH were acquired when metazoan organisms more than 500 million years ago developed an exo- or endoskeleton. This made it mandatory to control mechanisms of calcium carbonate or apatite formation, processes highly dependent on pH [12].

As discussed in this issue of Pflügers Archiv, virtually, all cells are equipped with pH-sensing and regulatory mechanisms. Proton-activated G protein-coupled receptors (GPCRs) can sense changes in extracellular pH. Interestingly, this ability is linked to sensing also flow, stiffness of extracellular matrix, or changes in calcium concentrations [8, 19]. Moreover, these receptors are also involved in various disease states. The example of inflammatory bowel disease highlights the complex and sometimes even antagonistic contribution of pH-sensing GPCRs to distinct aspects of the same disease process [10]. Also, molecules sensing intracellular pH or bicarbonate have been identified. Among them, the tyrosine kinase Pyk2 and soluble adenylyl cyclase [14]. The latter enzyme senses intracellular bicarbonate and is also involved in regulating acid–base transporters thereby controlling intra- and extracellular pH.

Diet, metabolism, and physical activity are major determinants whether our body experiences an acid or alkali load [21]. Western dietary habits with either highly processed food or diets rich in animal protein cause an acid load and this has been frequently associated with potential negative impacts on various organ functions such as bone stability, kidney stones, and more speculatively with cancer or metabolic derangements.

The kidneys play a central role in regulating and maintaining systemic pH by reabsorbing bicarbonate, by generating new bicarbonate through the process of ammoniagenesis and ammonium excretion, and by excreting acid, mostly under the form of so-called titratable acidity. Transport proteins along the nephron are involved in these processes and include Na+/H+-exchanger, Na+-dependent bicarbonate transporters, chloride-bicarbonate exchangers, and ammonia transporters [7, 11]. The kidneys adapt readily to changes in diet, metabolism, physical activity, or disease processes. These adaptations require mechanisms of acid–base sensing intrinsic to the kidney as well as by other organs. The anion exchanger AE4 appears to be critical for the ability of the collecting duct to adapt to changes in acid–base status [18]. AE4 is selectively expressed in type B intercalated cells which are mostly active during an alkali load or alkalosis. The very same cells are also a target of secretin. This hormone classically known as a stimulus for pancreatic juice production and bicarbonate secretion has recently emerged as a new and major regulator of renal bicarbonate secretion [2]. Type B intercalated cells are not only important for bicarbonate secretion, but link also this process to blood pressure regulation through the activity of two bicarbonate transporters pendrin and NDCBE that ultimately serve the reabsorption of chloride [5]. However, also type A intercalated cells, the main cells mediating urinary acidification and defective in forms of distal renal tubular acidosis, emerge with another unexpected feature, the ability to defend the kidney against urinary tract infections [16]. Ammoniagenesis contributes importantly to the kidney’s ability to regulate systemic pH as this process yields de-novo bicarbonate molecules. The excretion of the resulting ammonia involves several nephron segments, various ion transporters, and the ammonia transporters RhBG and RhCG [4].

The overall relevance of renal acid–base handling becomes very evident when individuals develop renal acidosis, e.g., the failure of the kidneys to contribute to acid–base balance due to either inherited forms of renal tubular acidosis or more globally due to renal failure. Interestingly, recent clinical trials and animal models suggest that kidney disease and acidosis may form a vicious circle where kidney disease causes acidosis, which in turn accelerates the progression of the disease [13].

Another example for the importance of controlling acid–base balance both on systemic and local levels comes from the cardiovascular system [3]. pH has a strong impact on blood flow and blood pressure regulation which in turn through oxygen delivery influences tissue pH. Likewise, cardiomyocytes are equipped with a series of acid–base transporters that link pH regulation to contractility and heart function.

Many organs or even intracellular organelles have distinct and specific acid–base domains that are required for organ or organelle-specific functions. In the brain, pH in the cerebrospinal fluid (CSF) needs to be tightly controlled as the function of neurons and other cells in the CNS are highly pH-dependent [6]. This involves various acid–base transporters located at the blood–brain barrier or choroid plexus. In contrast, large changes in intraluminal pH and bicarbonate content occur along the axis of the gastrointestinal tract and are critical for the specific functions of the stomach, the different segments of the small and the large intestine [1]. Again, distinct acid–base transport proteins [7, 11], pH sensors, and hormonal regulators are required and involved to coordinate this complex interplay between gastrointestinal segments. In patients with inflammatory bowel disease, inflammation alters local pH which modulates disease progression and severity [10].

Solid tumors have a distinct acid–base balance that is driven by the high metabolic rate of rapidly proliferating tumors, the relatively low oxygen availability, and the consequent shift of tumor cells to anaerobic glycolysis. Collectively, these processes lead to an acidic microenvironment in and around tumors [15, 20]. In order to survive and to continue proliferating, solid tumors often acquire different strategies to maintain intracellular pH by increasing the activity of pH-regulatory transporters as well as recruiting new blood vessels to improve oxygenation. Tumor cells regulate acid–base transporters in order to adapt to this acidic environment and to maintain a high proliferative rate [15, 20]. Acid-sensitive ion channels and proton-activated GPCRs may be involved in the adaption of tumor cells to their environment [9].

pH-sensitive channels and transporters as well as sensors of intra- and extracellular pH are also critically involved in migration of various types of cells such as tumor cells or immune cells [17]. Local pH gradients may even serve as chemoattractant to guide cell migration.

Collectively, this special issue explores the many ways mammalian cells and organs produce, sense, transport, neutralize, or respond to protons and other acid–base metabolites. The examples presented here provide compelling evidence of how important local and systemic acid–base balances are and how much they modulate normal physiology and contribute to disease states.