Relief of autoinhibition of the electrogenic Na-HCO₃cotransporter NBCe1-B: role of IRBIT vs. amino-terminal truncation

Abstract

Lee SK, Boron WF, Parker MD. Relief of autoinhibition of the electrogenic Na-HCO 3 cotransporter NBCe1-B: role of IRBIT vs. aminoterminal truncation.

IRBIT a Master Regulator of Cell Physiology

“…Using a heterologous system to co-express IRBIT and NBCe1-B, they showed by electrophysiological measurements that the transport activity of NBCe1-B is substantially increased in the presence of IRBIT [9]. Another study demonstrated that IRBIT increases NBCe1-B activity by masking in part the auto inhibitory domain of NBCe1-B [10]. These experiments suggest that IRBIT by increasing the activity of NBCe1-B, plays an important role in acid-base homeostasis.…”

Pathophysiological Roles of Mutations in the Electrogenic Na+-HCO - Cotransporter NBCe1

“…When expressed in Xenopus oocytes, NBCe1B and NBCe1C showed much lower activities than that of NBCe1A [66][67][68]. The deletion from of the cytoplasmic N-terminus of an 87-amino acid sequence markedly enhanced the activities of both NBCe1B and NBCe1C by more than 3-fold, indicating that this sequence contains an autoinhibitory domain [66,68].…”

“…The deletion from of the cytoplasmic N-terminus of an 87-amino acid sequence markedly enhanced the activities of both NBCe1B and NBCe1C by more than 3-fold, indicating that this sequence contains an autoinhibitory domain [66,68]. On the other hand, this sequence also contains a binding domain for inositol 1,4,5-triphosphate receptors (IP3R) binding protein released with IP3 (IRBIT).…”

“…Because this stimulation is not associated with the significant changes in the amount of NBCe1B expressed in the plasma membranes of Xenopus oocytes, IRBIT may induce the stimulation of per-molecule activity of NBCe1B [67,68]. Interestingly, Lee et al found that a mutant IRBIT lacking a protein phophatase-1 (PP-1) binding site stimulates NBCe1B to a 50% greater than can be achieved by the removal of autoinhibitory domain [68]. These results suggest that the stimulatory mechanism of IRBIT may involve not only the neutralization of autoinhibitory domain but also other factors.…”

“…In addition to the direct activation of NBCe1B and CFTR, IRBIT opposed the effects of WNKs and SPAK by recruiting PP-1 to dephosphorylate CFTR and NBCe1B, restoring their surface expression [72]. In contrast to these complex modes of IRBIT-mediated transport stimulation in secretory epithelia, the dephosphorylation of IRBIT by PP-1 may rather partially suppress the stimulatory effect of IRBIT on NBCe1B in Xenopus oocytes, which do not express WNKs or SPAK [68,73].…”