Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter

Abstract

Sodium-bicarbonate cotransporters are homologous membrane proteins mediating the electrogenic or electroneutral transport of sodium and bicarbonate. Of the functionally characterized sodium-bicarbonate cotransporters (NBC), NBC1proteins are known to be electrogenic. Here we report the cloning and functional characterization of NBC4c, a new splice variant of the NBC4 gene. At the amino acid level, NBC4c is 56% identical to NBC1 protein variants and 40% identical to electroneutral NBC3. When expressed in mammalian cells, NBC4c mediates electrogenic sodium-bicarbonate cotransport. The transport of sodium and bicarbonate is chloride independent and is completely inhibited by DIDS. NBC4c transcripts were detected in several tissues including brain, heart, kidney, testis, pancreas, muscle, and peripheral blood leukocytes. The data indicate that NBC4c is an electrogenic sodium-bicarbonate cotransporter. The finding that both NBC1 and NBC4c proteins function as electrogenic sodium-bicarbonate cotransporters will aid in determining the structural motifs responsible for this unique functional property, which distinguishes these transporters from other members of the bicarbonate transporter superfamily.

Sodium Bicarbonate Cotransporter Polymorphisms Are Associated With Baseline and 10-Year Follow-Up Blood Pressures

“…Chloride was measured because other family members of SLC4A5 are involved with chloride-dependent cotransport, although SLC4A5 acts in a chloride-independent manner. 11 If complete counterregulation of a NaHCO 3 transport defect does not occur through other systems, these plasma measurements may be altered. However, extracellular acid-base balance is important to maintain, minimizing the probability that significant alterations would be found in plasma Na or CO 2 .…”

Modular structure of sodium-coupled bicarbonate transporters

“…Of the six NBCe2 splice variants reported (Pushkin et al, 2000b;Sassani et al, 2002;Xu et al, 2003), only NBCe2a-d sequences are confirmed by the human genome database and of these four transcripts only NBCe2a and NBCe2c (see Fig. 4) include a full complement of TM segments.…”

“…NBCe1 also operates with a 1:2 stoichiometry when heterologously expressed in Xenopus oocytes (Heyer et al, 1999;Sciortino and Romero, 1999) and human embryonic kidney cells (Shao et al, 2008). This mechanistic flexibility (reviewed by Gross and Kurtz, 2002) is reported to be controlled by changes in [Ca 2+ ] (Muller-Berger et al, 2001) and may involve phosphorylation of the transporter (Gross et al, 2001b). Defective functional expression of NBCe1 is linked to proximal renal tubular acidosis (pRTA) (Igarashi et al, 1999), which can be associated with growth and mental retardation as well as ocular and dental defects (e.g.…”

“…As with NBCe1, the stoichiometry of NBCe2 is cell-type specific. For example, NBCe2 operates with an apparent Na + :HCO 3 -stoichiometry of 1:3 when heterologously expressed in the mPCT renal cell line (Sassani et al, 2002), but a 1:2 stoichiometry when heterologously expressed in Xenopus oocytes (Virkki et al, 2002).…”

Regulation of the Cardiac Sodium/Bicarbonate Cotransporter by Angiotensin II: Potential Contribution to Structural, Ionic and Electrophysiological Myocardial Remodelling

“…In the heart exist at least two electrogenic isoforms, called NBCe1 (also named NBC1) and NBCe2 (also named NBC4) which are encoded by the SLC4A4 gene [26], and the SLC4A5 gene [27], respectively, and one electroneutral isoform, named NBCn1 (also named NBC3), that is encoded by the SLC4A7 gene [28]. …”