The SLC4 transporter family, also known as the bicarbonate (HCO3^-)-transporter family, includes the products of ten human genes (SLC4A1-5; A7-11). In mammals, the SLC4 membrane proteins are critical for several physiological processes, including the carriage of carbon dioxide (CO₂) from the systemic capillaries to the pulmonary capillaries, the regulation of cell volume in multiple cell types, and the regulation of intracellular pH in nearly every cell of the body¹.

NBCe2 (NBC4) is an electrogenic sodium bicarbonate co-transporter encoded by SLC4A5. There are six NBCe2 isoform (SLC4A5A-F) reported². NBCe2 is an integral membrane protein consisting of 14 transmembrane domains. NBCe2 has a long N-terminal hydrophilic domain and a much shorter C-terminal hydrophilic domain, both of which are intracellular³.

NBCe2 is predominantly detected in the brain (highest in prefrontal cortex), epididymis, cardiac muscle, smooth muscle, kidney, and choroid plexus/apical¹.

Several studies identified SLC4A5 as a positional candidate for hypertension^4,5. In mice, disruption of slc4a5 causes both arterial hypertension as well as metabolic acidosis (distal renal tubular acidosis)⁶. In addition, mice lacking NBCe2 have reduced choroid plexus secretion and reduced ventricle size. These combined issues change intracranial pressure, CSF electrolytes, and cause severe eye pathologies such as photoreceptor loss, ganglion cell loss, and retinal detachment⁷.