Sodium-level-sensitive sodium channel and salt-intake behavior.

Mammals feel thirsty or develop an appetite for salt when the correct balance between water and sodium in the body fluid has been disrupted, but little is known about the mechanism in the brain that controls salt homeostasis. It has been postulated that the existence of both an osmoreceptor and a specific sodium receptor is required to accommodate the experimental data (Johnson and Edwards, 1990; Denton et al., 1996). Several candidate osmoreceptors have been reported (Oliet and Bourque, 1993; Wells, 1998; Liedtke et al., 2000); however, a specific sodium receptor has not been identified. The Nax channel—formerly called NaG/SCL11 (in rats), Nav2.3 (in mice) and Nav2.1 (in humans)—has been classified as a subfamily of voltage-gated sodium channels (Goldin et al., 2000). The primary structure of Nax, however, markedly differs from that of other voltage-gated sodium channel family members and includes differences in the key regions for voltage sensing and inactivation. The functional properties of the channel are poorly understood, as all attempts to induce functional expression of Nax in heterologous systems have failed. Several years ago, we generated mice in which the Nax gene was knocked-out by insertion of the lacZ gene in-frame and found that the Nax channel is expressed in cells in the circumventricular organs (CVOs) (Watanabe et al., 2000), in particular the subfornical organ (SFO) and organum vasculosum lamina terminalis (OVLT), which are important regions for the control of body fluid ionic balance; for the expression other than the CNS (see Watanabe et al., 2002). Under thirst conditions, Nax-deficient mice showed hyperactivity of the neurons in these two areas and ingested excessive salt: Wild-type mice take water and stop salt ingestion under dehydrated condition. Infusion of a hypertonic Na solution into the cerebral ventricle also induced extensive water intake and aversion to saline (0.3 M