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An N-terminal variant of Trpv1 channel is required for osmosensory transduction

Abstract

Body fluid homeostasis requires the release of arginine-vasopressin (AVP, an antidiuretic hormone) from the neurohypophysis. This release is controlled by specific and highly sensitive 'osmoreceptors' in the hypothalamus. Indeed, AVP-releasing neurons in the supraoptic nucleus (SON) are directly osmosensitive, and this osmosensitivity is mediated by stretch-inhibited cation channels. However, the molecular nature of these channels remains unknown. Here we show that SON neurons express an N-terminal splice variant of the transient receptor potential vanilloid type-1 (Trpv1), also known as the capsaicin receptor, but not full-length Trpv1. Unlike their wild-type counterparts, SON neurons in Trpv1 knockout (Trpv1−/−) mice could not generate ruthenium red–sensitive increases in membrane conductance and depolarizing potentials in response to hyperosmotic stimulation. Moreover, Trpv1−/− mice showed a pronounced serum hyperosmolality under basal conditions and severely compromised AVP responses to osmotic stimulation in vivo. These results suggest that the Trpv1 gene may encode a central component of the osmoreceptor.

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Figure 1: SON neurons express an N-terminal variant(s) of Trpv1.
Figure 2: Trpv1 is expressed in neurons of the PVN and SON.
Figure 3: Failure of osmosensory transduction in MNCs from Trpv1−/− mice.
Figure 4: The osmosensory transduction channel is a target for ruthenium red.
Figure 5: N-truncated Trpv1 variant is required for Ang II–induced excitation in MNCs.
Figure 6: Trpv1−/− mice show defects in systemic osmoregulation.

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Acknowledgements

We thank H. Gainer (US National Institute of Neurological Disorders and Stroke) for supplying the anti-AVP antibodies used in this study. We thank also S.H. Oliet, T. Stachniak, Z. Zhang, S. Ciura and E. Trudel for advice during the preparation of the manuscript. This work was supported by operating grants from the Canadian Institutes of Health Research (CIHR) to C.W.B. and P.S. Additional support was provided to C.W.B. through a CIHR Senior Investigator Award and a James McGill Research Chair. R.S.N. is a recipient of a CIHR Doctoral Award. P.S. is a Killam scholar.

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Correspondence to Charles W Bourque.

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Naeini, R., Witty, MF., Séguéla, P. et al. An N-terminal variant of Trpv1 channel is required for osmosensory transduction. Nat Neurosci 9, 93–98 (2006). https://doi.org/10.1038/nn1614

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