The direction of the response presumably depends on the pH-responsiveness of the individual channels, transporters, and receptors that are responsible for dictating overall excitability in each neuron. Note that the link between pH and neuronal excitability is not a simple one: some neurons (e.g., chemosensitive neurons) exhibit enhanced excitability in response to an acid-load, whereas others (e.g., hippocampal neurons) may exhibit reduced excitability. The relationship between pH and neuronal excitability has been extensively reviewed by others ( Balestrino and Somjen, 1988 Church, 1992 Tombaugh and Somjen, 1996 Dean et al., 2001 Makani and Chesler, 2007 Pavlov et al., 2013).
Table 1 list examples of pH sensitive proteins and activities involved in setting neuronal excitability. These properties endow neurons with the ability to communicate with other neurons and glial cells within the nervous system (for functions such as learning, behavior, conscious thought, and unconscious homeostatic regulation), and with cells outside the nervous system (for functions such as motor control and endocrine regulation). Together these proteins (1) govern the resting membrane potential of neurons, (2) affect neuronal responsiveness to agonists and antagonists, (3) set the threshold for firing an action potential, (4) influence the duration/amplitude of the action potential, (5) determine the length of the refractory period, and (6) synchronize neuronal network activity. The excitability of neurons is especially sensitive to changes in intracellular pH (pH i) and extracellular pH (pH o) due to the pH-sensitivity of intracellular and extracellular moieties on membrane proteins such as channels ( Tombaugh and Somjen, 1996 Duprat et al., 1997 Waldmann et al., 1997 Ruffin et al., 2008), transporters ( Irwin et al., 1994 Park et al., 2010 Adijanto and Philp, 2012), receptors ( Giffard et al., 1990 Tang et al., 1990 Traynelis and Cull-Candy, 1990 McDonald et al., 1998), and ATPase pumps ( Pick and Karlish, 1982 Wolosker et al., 1997). (4) The effect of acid-base disturbances on neuronal function and the roles of acid-base transporters in defending neuronal pH i under physiopathologic conditions. (3) The properties and importance of members of the SLC4 and SLC9 families of acid-base transporters expressed in the brain that contribute to J L (namely the Cl-HCO 3 exchanger AE3) and J E (the Na-H exchangers NHE1, NHE3, and NHE5 as well as the Na +- coupled HCO 3 − transporters NBCe1, NBCn1, NDCBE, and NBCn2). The balance between J E and J L determine steady-state pH i, as well as the ability of the cell to defend pH i in the face of extracellular acid-base disturbances (e.g., metabolic acidosis).
(2) pH i homeostasis and how it is determined by the balance between rates of acid loading ( J L) and extrusion ( J E). In this review, we will cover 4 major areas: (1) The effect of pH i on cellular processes in the brain, including channel activity and neuronal excitability.
Intracellular pH (pH i) regulation in the brain is important in both physiological and physiopathological conditions because changes in pH i generally result in altered neuronal excitability.
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