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Acid-base sensing and regulation: molecular mechanisms and functional implications in health and disease

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Acid-base disturbances alter the protonation state and charge of amino acids, thereby interfering with protein structure and function. Consequently, a normal level of intra- and extracellular pH is essential for cell and organ function, and acid-base disturbances have been suggested as important mechanistic ...

Acid-base disturbances alter the protonation state and charge of amino acids, thereby interfering with protein structure and function. Consequently, a normal level of intra- and extracellular pH is essential for cell and organ function, and acid-base disturbances have been suggested as important mechanistic components in disease development.

Most cells are inherently susceptible to becoming acidotic because cellular metabolism produces intracellular acid, and the electrochemical proton gradient favors the passive influx of acid equivalents (or efflux of base equivalents) across the cell plasma membrane. In addition, the flux of specific gases (e.g., CO2 and NH3) through either the lipid bilayer or selective ion or gas channels will also alter pH. Accordingly, a number of primary and secondary active transport mechanisms for e.g. H+, HCO3- and carboxylates are in place to maintain acid-base homeostasis.

Acid-base balance is often challenged by both physiological and pathophysiological conditions. Changes in pH are evident with increased metabolism (e.g., during exercise and neuronal activity), as well as in disease states particularly associated with insufficient blood supply (e.g., cancer and stroke/ischemia).

Appropriate homeostatic responses under these circumstances depend on the ability of the body to sense acid-base disturbances; and over the previous years, a number of cellular sensors for CO2, HCO3- and pH have been proposed.

The cellular and molecular mechanisms of acid-base regulation have been extensively studied during the past decades, and most of the described acid-base transport mechanisms have now been assigned to specific proteins that have been genetically identified. Despite groundbreaking molecular observations, many physiological and pathophysiological aspects of acid-base regulation and sensing remain undetermined. High resolution structures of the transport and sensing proteins, for instance, are remarkably sparse. Likewise, the functional consequences of splice variation, sub-cellular distribution patterns, interactions with binding partners and putative phosphorylation-sites of the transport proteins need further investigation. Such characteristics likely impart the transporters with a dynamic regulatory potential during cellular responses to acute or chronic acid-base disturbances. It is noteworthy that although acid-base disturbances have been known to modulate physiological function (e.g., artery contraction) for more than a century, the pH-sensitive targets responsible for these functional adjustments are poorly understood.

According to results from animal studies, disturbed acid-base regulation or sensing has substantial consequences for cardiovascular, gastrointestinal, renal, ocular and neurological function. Additionally, recent epidemiological studies have demonstrated a number of associations between human disease and polymorphisms in acid-base related genes. It is an ongoing challenge to investigate the effects of acid-base disturbances on integrated physiological functions, and to determine the functional background linking genetic variations to relevant disease pathogenesis.

The current research topic aims to support the progress towards understanding the role of acid-base regulatory and sensing mechanisms under physiological conditions, and the contribution from intra- and extracellular acid-base disturbances to the development of disease. Studies ranging from the molecular and cellular level to the integrated organ and organism level are encouraged. The topic is open to original studies covering experimental and theoretical approaches, descriptions of new methodologies, reviews and opinions.


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