A-type K⁺ channels contribute to the prorenin increase of firing activity in hypothalamic vasopressin neurosecretory neurons

Abstract

Recent studies have supported an important contribution of prorenin (PR) and its receptor (PRR) to the regulation of hypothalamic, sympathetic, and neurosecretory outflows to the cardiovascular system, including systemic release of vasopressin (VP), both under physiological and cardiovascular disease conditions. Still, the identification of precise cellular mechanisms and neuronal/molecular targets remain unknown. We have recently shown that PRR is expressed in VP neurons and that their activation increases neuronal activity. However, the underlying ionic channel mechanisms are undefined. Here, we performed patch-clamp electrophysiology from identified VP neurons in acute hypothalamic slices obtained from enhanced green fluorescent protein-VP transgenic rats. Voltage-clamp recordings showed that PR inhibited the magnitude of A-type K current (; ~50% at -25 mV), a subthreshold voltage-dependent current that restrains VP firing activity. PR also increased the inactivation rate of and shifted the steady-state voltage-dependent inactivation function toward more hyperpolarized membrane potential (~7 mV shift), thus resulting in less channel availability to be activated at any given membrane potential. PR also inhibited a sustained component of ("window" current). PR-mediated changes in action potential waveform and increased firing activity were occluded when was blocked by 4-aminopyridine. Finally, PR failed to increase superoxide production within the supraoptic nucleus/paraventricular nucleus, and PR excitatory effects persisted in slices treated with the SOD mimetic tempol. Taken together, these experiments indicated that PR excitatory effects on vasopressin neurons involve inhibition of, due, in part, to increases in its voltage-dependent inactivation properties. Moreover, our results indicate that PR effects did not involve an increase in oxidative stress. Here, we demonstrate that prorenin/the prorenin receptor is an important signaling unit for the regulation of vasopressin firing activity and, thus, systemic hormonal release. We identified A-type K channels as key molecular targets mediating prorenin stimulation of vasopressin neuronal activity, thus standing as a potential therapeutic target for neurohumoral activation in cardiovascular disease.

Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels

“…While the latter decreases tonic firing frequencies, the total number of APs elicited by a given depolarizing pulse is increased, thus demonstrating the limitation of AP firing by I A . This view is corroborated by findings from different neuronal cell types where receptor stimulation-dependent activation and inhibition of I A reduces and increases the rate of firing APs, respectively (Kloppenburg et al 1999 ; Pitra and Stern 2017 ). In a similar way the knock down of Kv4.1 channels increased neuronal firing rates (Hermanstyne et al 2017 ).…”

Exacerbated effects of prorenin on hypothalamic magnocellular neuronal activity and vasopressin plasma levels during salt-sensitive hypertension

“…Thus, it is reasonable to speculate that the PRR-mediated increase of VP levels in DOCA-salt hypertension involved changes in MNN membrane excitability and/or firing activity. We recently reported that PRR receptors are densely expressed both in VP and oxytocin MNNs and that their activation evokes an excitatory effect, leading to an increase in their firing activity (41,42). These effects were ANG II independent, requiring an increase in intracellular Ca 2ϩ levels (41), as well as an inhibition of the I A (42).…”

“…We recently reported that PRR receptors are densely expressed both in VP and oxytocin MNNs and that their activation evokes an excitatory effect, leading to an increase in their firing activity (41,42). These effects were ANG II independent, requiring an increase in intracellular Ca 2ϩ levels (41), as well as an inhibition of the I A (42). The later effect involved an increased rate of I A inactivation and a shift in the steady-state voltage-dependent inactivation function toward more hyperpolarized membrane potentials (42).…”

“…These effects were ANG II independent, requiring an increase in intracellular Ca 2ϩ levels (41), as well as an inhibition of the I A (42). The later effect involved an increased rate of I A inactivation and a shift in the steady-state voltage-dependent inactivation function toward more hyperpolarized membrane potentials (42).…”

“…PRR is highly expressed in these nuclei (26,27,45), predominantly in magnocellular neurosecretory neurons (MNNs), including both VP and oxytocin neurons in rats (41). Moreover, we recently showed that focal application of PR in MNNs increased their firing activity (41) an effect mostly mediated by inhibition of voltage-gated A-type K ϩ channels (42).…”