Table 1.

Acid-base sensors in kidney tubule epithelial cells

Pyk2Low intracellular and intraluminal pH within the proximal tubuleNHE3, proton secretionPyk2 autophosphorylation and kinase activity are activated by low pH (<7.4), which stimulates NHE3 expression leading to proton secretion6568
ETB receptor pathwayLow intracellular and intraluminal pH within the proximal tubuleNHE3, proton secretionERK1/2, and c-fos transcriptional activation of ET-1 and ETB receptors leads to NHE3 membrane accumulation and increased proton secretion68,69
Erb1/2 heterodimer, receptor protein tyrosine phosphatase-γ, angiotensin receptor AT1AIncreased basolateral CO2Bicarbonate reabsorption in proximal tubulesErb1/2 and AT1A receptor pathways sense basolateral CO2 and bicarbonate levels and activate appropriate level of bicarbonate reabsorption7073
GPR4Low blood and interstitial pH, low urinary pH in collecting ductProton secretion mediated by cAMP and V-ATPase translocation in A-type intercalated cellsGPR4 increases intracellular cAMP and IP3 when complexed with proton7477
Soluble adenyl cyclaseBicarbonate anionMonitors extracellular acid-base balance in the kidney tubulesSoluble adenyl cyclase produces cAMP, which directly stimulates V-ATPase membrane accumulation and proton secretion; regulates V-ATPase–mediated proton transport in tubules7882
V-ATPasepH in the proximal tubuleSensor of intraluminal and intracellular pHV-ATPase has both proton-sensing and transport functions; V-ATPase forms a complex with other apical proteins to transport proton into the tubule lumen; sensor component works in concert with soluble adenyl cyclase83,84
  • Pyk2, nonreceptor tyrosine kinase; ERK1/2, protein-serine/threonine kinases that participate in the Ras/Raf/mitogen-activated protein kinase kinase/ERK signal transduction cascade; c-fos, a proto-oncogene that is the human homolog of the retroviral oncogene v-fos; Erb1/2, receptor tyrosine kinases which are structurally related to the epidermal growth factor receptor (EGFR); AT1A, fibroblast angiotensin II type 1a receptor; CO2, carbon dioxide; V-ATPase, vacuolar (H+)-ATPase which is an ATP-dependent proton pump that functions to acidify intracellular compartments and transport protons across the plasma membrane of eukaryotic cells; IP3, inositol triphosphate.