Vasopressin receptors V1(a) and V2 are not osmosensors

Herein, we investigated whether G protein-coupled signaling via the vasopressin receptors of the V1(a) and V2 subtypes (V1(a)R and V2R) could be obtained as a direct response to hyperosmolar challenges and/or whether hyperosmolar challenges could augment classical vasopressin-dependent V1(a)R signaling. The V1(a)R-dependent response was monitored indirectly via its effects on aquaporin 4 (AQP4) when heterologously expressed in Xenopus oocytes and V1(a)R and V2R function was directly monitored following heterologous expression in COS-7 cells. A tendency toward an osmotically induced, V1(a)R-mediated reduction in AQP4-dependent water permeability was observed, although osmotic challenges failed to mimic vasopressin-dependent V1(a)R-mediated internalization of AQP4. Direct monitoring of inositol phosphate (IP) production of V1(a)R-expressing COS-7 cells demonstrated an efficient vasopressin-dependent response that was, however, independent of hyperosmotic challenges. Similarly, the cAMP production by the V2R was unaffected by hyperosmotic challenges although, in contrast to the V1(a)R, the V2R displayed an ability to support alternative signaling (IP production) at higher concentration of vasopressin. V1(a)R and V2R respond directly to vasopressin exposure, but they do not have an ability to act as osmo- or volume sensors when exposed to an osmotic gradient in the absence or presence of vasopressin.