Na+‐K+‐2Cl−Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia

Two genes encode the Na+-K+-2Cl− cotransporters, NKCC1 and NKCC2, that mediate the tightly coupled movement of 1Na+, 1K+, and 2Cl− across the plasma membrane of cells. Na+-K+-2Cl− cotransport is driven by the chemical gradient of the three ionic species across the membrane, two of them maintained by the action of the Na+/K+ pump. In many cells, NKCC1 accumulates Cl− above its electrochemical potential equilibrium, thereby facilitating Cl− channel-mediated membrane depolarization. In smooth muscle cells, this depolarization facilitates the opening of voltage-sensitive Ca2+ channels, leading to Ca2+ influx, and cell contraction. In immature neurons, the depolarization due to a GABA-mediated Cl− conductance produces an excitatory rather than inhibitory response. In many cell types that have lost water, NKCC is activated to help the cells recover their volume. This is specially the case if the cells have also lost Cl−. In combination with the Na+/K+ pump, the NKCC's move ions across various specialized epithelia. NKCC1 is involved in Cl−-driven fluid secretion in many exocrine glands, such as sweat, lacrimal, salivary, stomach, pancreas, and intestine. NKCC1 is also involved in K+-driven fluid secretion in inner ear, and possibly in Na+-driven fluid secretion in choroid plexus. In the thick ascending limb of Henle, NKCC2 activity in combination with the Na+/K+ pump participates in reabsorbing 30% of the glomerular-filtered Na+. Overall, many critical physiological functions are maintained by the activity of the two Na+-K+-2Cl− cotransporters. In this overview article, we focus on the functional roles of the cotransporters in nonpolarized cells and in epithelia. © 2018 American Physiological Society. Compr Physiol 8:871-901, 2018.