Gating by osmosis

Ca²⁺ influx into a cell that expresses VR-OAC. In the presence of hypotonic solution (arrow down), the intracellular Ca²⁺ concentration increases in the transfected cell (right). This effect is reversible in the presence of hypertonic solution (arrow up).

Osmosis is arguably one of the earliest biological concepts that we learn; the image of a cell swelling or shrinking in response to changes in osmolarity is certainly one of the oldest memories I keep from my early days in school. How do cells respond and adapt to changes in osmotic pressure? It is surprising that our understanding of osmosis from this standpoint is still quite limited. Similarly, although we know that the nervous system is crucial in osmoregulation, controlling the release of vasopressin and the subsequent production of urine, so far we only have a mere glimpse of the brain mechanisms underlying osmoreception. But now, a paper by Liedtke et al. on the cloning of the first osmotically activated channel found in vertebrates could be the breakthrough we needed to get a molecular handle on this problem.

The authors identified a vanilloid receptor-related osmotically activated channel ( VR-OAC) by looking for vertebrate homologues of Osm-9 — a mechanosensitive channel from Caenorhabditis elegans whose product confers sensitivity to osmotic pressure. VR-OAC is related to the vanilloid receptor VR1 and belongs to the transient receptor potential family of channels, molecules with six transmembrane segments and a pore domain analogous to most voltage-gated ion channels. Although it was most abundant in the kidney, VR-OAC was also found in several brain regions including the circumventricular organs (areas devoid of blood–brain barrier and implicated in the control of vasopressin release and water intake) and the median preoptic area (a region important for the regulation of drinking behaviour).

VR-OAC was gated by subtle reductions of osmotic pressure in transfected cells. Hypotonic solutions activated the channel in a graded manner and led to the release of calcium from intracellular pools. In addition, VR-OAC had a large unitary conductance and showed marked outward rectification in the presence of extracellular calcium, implying that when cells swell, ion flux will occur predominantly out of the cell.

It will be important to determine the mechanism whereby the different cell populations that express VR-OAC in the brain transduce changes in osmolarity to keep its homeostatic value and to test whether channel opening alters the firing properties of those neurons. Similarly, it will be interesting to determine whether VR-OAC can function as a stretch-activated channel in the inner ear and the Merkel receptors, structures that express VR-OAC and transduce mechanical into electrical activity. Last, the observation that VR-OAC is not gated by hypertonic stimuli indicates that this channel may only be the first part of an exciting story.