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Symposium Reports |
1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA 2 Department of Medicine, Georgetown University, Washington, DC 20007, USA
Email: stricker{at}bns.pitt.edu
This issue contains four papers based on a symposium entitled Hydromineral Neuroendocrinology, which took place at the International congress of Neuroendocrinology in Pittsburgh, PA, USA, June 2006.
Osmoregulation and volume regulation, and body fluid balance generally, are accomplished for the most part by two central systems, one that controls thirst and drinking behaviour and one that controls neurohypophyseal secretion of the peptide hormone arginine vasopressin (AVP; Stricker & Verbalis, 2002; Stricker, 2004). Signals emanating from the systemic circulation are known to influence both of these central control systems. For example, increases in systemic plasma osmolality (pOsm) stimulate thirst and secretion of AVP, which increases membrane permeability in the distal tubules and collecting ducts in the kidney, thereby increasing water reabsorption and the concentration of excreted urine. By this combination of effects on renal function and drinking behaviour, systemic pOsm usually is maintained within a normal range that varies only by 1–2%. Relevant osmoreceptors that mediate these effects have been discovered in the organum vasculosum of the lamina terminalis (OVLT) in the basal forebrain. These osmoreceptors can respond to elevations in systemic pOsm because the OVLT lacks a blood–brain barrier, thus allowing osmotic fluxes of water in and out of local neurones.
A second major stimulus of AVP secretion and thirst is a reduction in blood volume (hypovolaemia), mediated by cardiac baroreceptors. Conversely, an increase in blood volume inhibits AVP secretion caused by increased pOsm, although it does not inhibit osmotic thirst. A third stimulus results from acute arterial hypotension. Mediation of thirst by the renin–angiotensin system has been well established, with angiotensin II (Ang II) providing the stimulus by acting on Ang II AT1 receptors in the subfornical organ (SFO), another circumventricular organ that lacks a blood–brain barrier. Ang II also appears to act centrally to stimulate salt appetite. Hypovolaemia-induced stimulation of AVP secretion appears to result in part directly through Ang II, and in part through activation of arterial baroreceptors in the aortic arch and carotid sinus.
This symposium reports four papers that address key issues in the central control of body fluid homeostasis. The on-going research described ranges from cellular and molecular neurobiological investigations to whole animal studies.
The first two papers present intriguing new data regarding the neural cells that sense changes in osmolality and the molecular mechanisms by which they do so. The first paper, by Bourke and co-workers (Montreal, Canada), describes a detailed series of studies of osmosensory neurones in the OVLT (Bourque et al. 2007). Based in part on their results showing that these OVLT neurones display changes in action potential firing rate that vary in proportion to the osmolality of extracellular fluid, they propose that the cells represent primary osmosensory neurones. Osmotically evoked changes in the firing rate of OVLT neurones then synaptically regulate the electrical activity of downstream effector neurones in the supraoptic nucleus through graded changes in glutamate release. The cellular osmosensing mechanism used by the OVLT cells appears to be an intrinsic depolarizing receptor potential, which these cells generate via a molecular transduction complex. Although not yet fully characterized, results suggest that this probably includes members of the transient receptor potential vanilloid (TRPV) family of cation channel proteins.
The second paper, by Liedtke (Duke, USA), describes in greater detail molecular studies of the TRPV family of cation channel proteins, and presents evidence supporting roles for TRPV1, TRPV2 and TRPV4 channels in the transduction of osmotic stimuli in mammals (Liedtke, 2007). Specifically, TRPV1 knockout mice have been found to have defects in osmotically stimulated AVP secretion, and TRPV4 knockout mice similarly manifest impaired AVP secretion and drinking responses to induced hyperosmolality, implicating both of these channels in osmotic sensing of hyperosmolality. As further proof of this concept, mammalian TRPV4 has been found to rescue osmosensory deficits of the TRPV mutant strain osm-9 in Caenorhabditis elegans. Since there is only limited homology between TRPV4 and osm-9, this represents a striking example of evolutionary conservation of function with regard to primary osmoregulatory mechanisms.
Although the details of exactly how and where various members of the TRPV family of cation channel proteins participate in osmoregulation in different species remains to be ascertained by further studies, these complimentary papers make a very strong case for their integral involvement in the transduction of osmotic stimuli in the neural cells that regulate osmotic homeostasis, which appears to have been be highly conserved throughout evolution.
The last two papers of the symposium focus on aspects of sodium homeostasis. Although cerebral osmoreceptors plainly provide control over thirst and AVP secretion, there is evidence that putative cerebral sodium receptors make an independent contribution to body fluid homeostasis. However, it has never been clear whether cerebral sodium receptors exist. The third paper, by Noda (Okazaki, Japan), summarizes a series of recent experiments that demonstrate the existence of such receptors and characterize some of their properties (Noda, 2007). They focus on Nax, the recently found, atypical type of sodium channel that appears to be specifically sensitive to extracellular sodium concentrations above 150 mM (the concentration of isotonic fluid).
Animals adaptively consume water and avoid hypertonic NaCl solutions when osmolality in blood and cerebrospinal fluid (CSF) is increased. However, mutant mice lacking the gene for the Nax channel do not behave as normal mice do. In contrast, when the Nax gene is introduced into the SFO of Nax–/– mice (but not elsewhere in the brain), the response of avoiding concentrated NaCl solution when dehydrated is recovered. The Nax channel has been found in the OVLT and SFO but it is not localized in neurones; instead, it is located in inexcitable glial cells. Those observations have led to the novel idea that brain sodium sensing occurs in glial cells, which envelope local neurones, activate them, and thereby set into motion adaptive decreases in NaCl intake whenever the CSF sodium concentration is elevated. It remains to be determined whether other brain cells detect decreases in CSF sodium or are involved in the initiation of salt appetite.
The fourth paper, by Daniels et al. (Penn, USA), addresses the cellular mechanisms by which Ang II, acting in the brain, stimulates thirst or salt appetite in rats (Daniels et al. 2007). Theoretically, one possibility is that Ang II stimulates one motivation or the other depending on what other signals are present simultaneously. For example, the presence of aldosterone in rats promotes salt appetite, whereas the activation of central oxytocin neurones appears to inhibit salt appetite and promote thirst (Stricker & Verbalis, 1996). An alternative view, not mutually exclusive with the first, is supported by findings suggesting that Ang II acts at a G protein-coupled receptor in the brain to stimulate thirst when one intracellular signal transduction pathway is activated (involving the formation of the second messengers inositol triphosphate and diacylglycerol), and it stimulates salt appetite when a different pathway is activated (involving the activation of MAP kinase).
Collectively, these four papers present exciting new results at the forefront of studies of how the brain controls body fluid homeostasis.
References
Bourque CW et al (2007). Neurophysiological charactisation of osmosensitive neurons. Exp Physiol 92, 499–505.
Daniels D, Yee DK & Fluharty SJ (2007). Angiotensin II receptor signaling. Exp Physiol 92, 523–527.
Liedtke W (2007). Role of TRPV ion channels in sensory transduction of osmotic stimuli in mammals. Exp Physiol 92, 507–512.
Noda M (2007). Hydromineral neuroendocrinology: mechanism of sensing sodium levels in the mammalian brain. Exp Physiol 92, 513–522.
Stricker EM (2004). Thirst. In Handbook of Behavioral Neurobiology, vol. 14, ed. Stricker EM & Woods SC, pp. 505–543. Kluwer Academic/Plenum, New York.
Stricker EM & Verbalis JG (1996). Central inhibition of salt appetite by oxytocin in rats. Reg Peptides 66, 83–85.[CrossRef][Medline]
Stricker EM & Verbalis JG (2002). Fluid intake and homeostasis. In Fundamental Neuroscience, 2nd edn, ed. Squire LR, Bloom FE, Roberts JL, Zigmond MJ, McConnell SK & Spitzer NC, pp. 991–1009. Academic Press, San Diego.
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