Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
Sodium-level-sensitive Sodium Channel and Salt-Intake Behavior
Division of Molecular Neurobiology, National Institute for Basic Biology and The Department of Molecular Biomechanics, The Graduate University for Advanced Studies, Okazaki, Aichi 444-8787, Japan
Correspondence to be sent to: Masaharu Noda, e-mail: madon{at}nibb.ac.jp
Key words: circumventricular organs, subfornical organ, organum vasculosum lamina terminalis, thirst, adenoviral gene transfer, gene knockout mice
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 NaCl) in wild-type animals, but not in the knockout mice (unpublished data): The Nax-deficient mice did not show aversion to saline. Importantly, the aversion to salt was not induced by infusion of a hyperosmotic mannitol solution with physiological Na concentration in both genotypes of mice (unpublished data).
These findings led us to propose that Nax is involved in the sodium-level
sensing mechanism in the brain. We verified this possibility by imaging analysis of
changes in the intracellular sodium-ion concentration
[Na+]i when the extracellular sodium-ion
concentration [Na+]o was raised stepwise from the
normal amount (Hiyama et al.,
2002). When [Na+]o was increased from
the control amount of 145 mM (physiological level) to 170 mM by bath application, the
[Na+]i of some cells dissociated from the SFO of
wild-type mice showed a pronounced increase (Figure
1A,B). Importantly, all the responsive
cells were Nax-immunoreactive. These neurons responded to the rise in
[Na+]o, but not to the rise in osmolarity or
[Cl–]o (Figure
1C). Tetrodotoxin (TTX) at 1 µM
did not antagonize the response (Figure
1C).
[Na+]o at the half-maximal
(C1/2) was 157 mM (Figure
1D). When
Nax cDNA was introduced into the dissociated SFO cells
derived from Nax-deficient mice,
[Na+]i response similar to that in wild-type cells
appeared (Figure
2). Thus, Nax is a
newly identified type of sodium channel that is sensitive to an increase in the
extracellular sodium concentration.
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Sodium concentrations in the plasma and CSF increase by 5–10% during thirst conditions (Nose et al., 1992
). The sensitivity and threshold of Nax channels to
[Na+]o is in this range of physiological change. The
CVOs including SFO and OVLT are regions where the blood–brain barrier is missing,
enabling cells to directly monitor body fluid conditions. When
Nax cDNA was introduced into the brain of the knockout mice
with adenoviral expression vector, animals that received transduction of the
Nax gene into the SFO among the CVOs regained the
salt-avoiding behavior under dehydrated conditions (unpublished data). This indicates
that Nax channel in the SFO is essential and sufficient for the
control of salt-intake behavior. Taken together, we advocate that SFO is the principal
site for the control of salt-intake behavior, where Nax channel
functions as the Na-level sensor.
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