Physiological carbon dioxide, bicarbonate, and pH sensing

Abstract

In biological systems, carbon dioxide exists in equilibrium with bicarbonate and protons. The individual components of this equilibrium (i.e., CO₂, HCO₃⁻, and H(+)), which must be sensed to be able to maintain cellular and organismal pH, also function as signals to modulate multiple physiological functions. Yet, the molecular sensors for CO₂/HCO₃⁻/pH remained unknown until recently. Here, we review recent progress in delineating molecular and cellular mechanisms for sensing CO₂, HCO₃⁻, and pH.

Fig. 1

Extracellular pH/CO₂ sensing by H⁺-gated channels in sensory neurons. a Extracellular H⁺, which could derive from elevated CO₂ (b), stimulate cation currents. Examples include TRP channels, such as PKD2L1 and TRPV1, and ASICs. If coexpressed with extracellular carbonic anhydrase IV (CA_IV), these channels can indirectly sense extracellular CO₂

Fig. 2

Intracellular pH sensing by the tyrosine kinase Pyk2 in the renal proximal tubule. a Intracellular H⁺ activate PyK2 and c-Src, which promote apical H⁺ secretion and Na⁺ absorption by b sodium hydrogen exchanger 3 (NHE3) and c Na⁺ and HCO₃⁻ absorption by sodium bicarbonate cotransporter (NBC)

Fig. 3

Activation of sAC inside the cells. Production of cAMP by sAC can be modulated by HCO₃⁻ which a originates via carbonic anhydrase (CA) hydration of exogenous CO₂, b enters the cell via sodium bicarbonate cotransporter (NBC), or c is generated from metabolic CO₂ production inside mitochondria

Fig. 4

Sensing and regulation of systemic pH and acid/base status by carbonic anhydrase (CA), sAC, and vacuolar proton pump (VHA). Alkalosis due to elevated extracellular HCO₃⁻ and/or pH results in elevated extracellular CO₂, a reaction catalyzed by extracellular CA_IV. CO₂ diffuses inside the cell, where it is hydrated into H⁺ and HCO₃⁻. sAC is activated by intracellular HCO₃⁻ to produce cAMP, which promotes (via PKA) the insertion of VHA-containing vesicles into the cell membrane facing the alkalosis. Membrane-inserted VHAs secrete H⁺, which counteract the alkalosis. sAC may also modulate the activity of HCO₃⁻ transporters in the opposite membrane. In the clear cells of the epididymis and in A-type renal intercalated cells, Side A is the apical (mucosal) side and Side B is the basolateral (serosal) side. The polarity is reversed in base-secreting cells of the shark gill and in B-type renal intercalated cells