NAD is known as a coenzyme for many enzymes catalyzing redox reactions or
as a substrate for enzymes for second messenger cADP-ribose generation or
protein deacetylation. IRBIT and L-IRBIT are structurally conserved with
dehydrogenases but lacking catalytic activity. By protein interaction, the
IRBITs instead modulate many proteins of fundamental biological
importance. Among these is the Na+-HCO3− cotransporter NBCe1-B, which
plays a central role in intracellular pH (pHi) regulation and epithelial
electrolyte transport. Here, we demonstrate that NAD modulates NBCe1-B
activation by serving as a cofactor of the IRBITs. Blocking NAD salvage
pathway decreases NBCe1-B activation by the IRBITs. NAD+ administration
enhances, whereas NADH decreases NBCe1-B activity. Our study reveals a new
role of NAD and greatly expands our appreciation of NAD biology. Because
NAD redox state fluctuates greatly with metabolic status, our work
provides insight into how, via IRBITs, energy metabolism could affect pHi
regulation and many other IRBIT-dependent processes.