Peptidergic excitation of supraoptic nucleus neurons: involvement of stretch-inactivated cation channels.

Although the primary stimulus regulating vasopressin (VP) release is a change in systemic osmolality, other physiological parameters are known to affect VP secretion or modulate the osmotic control over its release. Neuropeptides feature prominently in afferents underlying the central regulation of the VP-releasing magnocellular neurosecretory cells (MNCs). Although little is yet known of the circumstances under which peptides are released onto MNCs, previous studies have shown that a common response profile to exogenous peptide application is a slow excitation that seems to result from the activation of a nonselective cation conductance. In this paper we review the basis for the excitatory effects of angiotensin II, cholecystokinin, and neurotensin in MNCs acutely isolated from the supraoptic nucleus of adult rats. Saturating concentrations of these three peptides evoked nonadditive increases in macroscopic cation conductance. During single-channel recordings Ang II, CCK, and NT caused kinetically identical increases in the probability of opening of 35-pS nonselective cation channels. Patches containing only one channel further revealed that the activity of single channels could be regulated by separate applications of all three peptides. Peptide-stimulated channels were also found to be inactivated by increases in membrane stretch and to be blocked by low concentrations of gadolinium (Gd(3+)). It is concluded that many excitatory peptides depolarize MNCs by stimulating the stretch-inactivated cation channels underlying osmoreception. Convergent regulation of these channels provides a potentially powerful mechanism for integrating signals derived from the various afferents involved in the regulation of MNCs.

Excitatory peptides and osmotic pressure modulate mechanosensitive cation channels in concert.

Behavioral and neuroendocrine responses underlying systemic osmoregulation are synergistically controlled by osmoreceptors and neuropeptides released within the hypothalamus. Although mechanisms underlying osmoreception are understood, the cellular basis for the integration of osmotic and peptidergic signals remains unknown. Here we show that the excitatory effects of angiotensin II, cholecystokinin and neurotensin on supraoptic neurosecretory neurons are due to the stimulation of the stretch-inactivated cation channels responsible for osmoreception. This molecular convergence underlies the facilitatory effects of neuropeptides on responses to osmotic stimulation and provides a basis for the gating effects of plasma osmolality on the responsiveness of osmoregulatory neurons to peptidergic stimulation.

Coincident detection of CSF Na+ and osmotic pressure in osmoregulatory neurons of the supraoptic nucleus.

Behavioral and neuroendocrine responses underlying systemic osmoregulation are under the concerted control of centrally located osmoreceptors and cerebrospinal fluid (CSF) Na+ concentration ([Na+]) detectors. Although the process underlying osmoreception is understood, the mechanism by which [Na+] is detected and integrated with cellular information derived from osmoreceptors is unknown. Here, we show that shifts in extracellular [Na+] ([Na+]0) cause proportional changes in the relative Na+ permeability of mechanosensitive cation channels responsible for signal transduction in the osmosensory neurons of the supraoptic nucleus. This effect causes the generation of Na+ specific receptor potentials under isotonic conditions and modulates osmoreceptor potentials and electrical responsiveness during osmotic perturbation. These results provide a cellular basis for Na+-sensing and for the coordinated detection of CSF [Na+] and osmolality in central osmoregulatory neurons.