Actions of a hydrogen sulfide donor (NaHS) on transient sodium, persistent sodium, and voltage-gated calcium currents in neurons of the subfornical organ

Abstract

Hydrogen sulfide (H2S) is an endogenously found gasotransmitter that has been implicated in a variety of beneficial physiological functions. This study was performed to investigate the cellular mechanisms underlying actions of H2S previously observed in subfornical organ (SFO), where H2S acts to regulate blood pressure through a depolarization of the membrane and an overall increase in the excitability of SFO neurons. We used whole cell patch-clamp electrophysiology in the voltage-clamp configuration to analyze the effect of 1 mM NaHS, an H2S donor, on voltage-gated potassium, sodium, and calcium currents. We observed no effect of NaHS on potassium currents; however, both voltage-gated sodium currents (persistent and transient) and the N-type calcium current had a depolarized activation curve and an enhanced peak-induced current in response to a series of voltage-step and ramp protocols run in the control and NaHS conditions. These effects were not responsible for the previously observed depolarization of the membrane potential, as depolarizing effects of H2S were still observed following block of these conductances with tetrodotoxin (5 μM) and ω-conotoxin-GVIA (100 nM). Our studies are the first to investigate the effect of H2S on a variety of voltage-gated conductances in a single brain area, and although they do not explain mechanisms underlying the depolarizing actions of H2S on SFO neurons, they provide evidence of potential mechanisms through which this gasotransmitter influences the excitability of neurons in this important brain area as a consequence of the modulation of multiple ion channels.

Hydrogen sulfide inhibits Kir2 and Kir3 channels by decreasing sensitivity to the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2)

“…H 2 S mediates ischemic damage pursuant to stroke in neuronal tissue (15), whereas it serves as a powerful cardioprotective agent upon comparable conditions. One categorical correlation that emerged in the studies highlighting this 'dual physiological effect' by the gaseous mediator is that while H 2 S depolarizes cerebral components (8)(9)(10)(11)(12), it hyperpolarizes cardiomyocytes (13,14). In other words, H 2 S increases the excitability of cerebral tissue, worsening seizure-like symptoms and rendering neurons more susceptible to ischemic insult (12,15).…”

“…Thus, subsequent efforts have been made to identify key ion channels that contribute to the depolarizing effect of H 2 S on neuronal cells. To date, the identity of H 2 S-sensitive ion channels in specific neuronal tissues has remained elusive (8)(9)(10)(11)(12). Relying on ion channel blockers with limited specificity has made it difficult to reliably correlate the effect of H 2 S on observed depolarizations in neurons to specific ion channels.…”

“…Collectively, H 2 S has been shown to play a role in diverse physiological processes, such as cellular necrosis, apoptosis, oxidative stress, or inflammation (7). One theme emerging from these studies is that H 2 S increases the excitability of neuronal compartments (8)(9)(10)(11)(12), whereas it depresses excitability of cardiac tissues (13,14), correlating to neurotoxic (12,15) and cardioprotective (16)(17)(18)(19)(20) effects, respectively. Therefore, exactly how H 2 S is affecting differentially ion channels expressed in cells that rapidly control membrane excitability has become a central question.…”

The subfornical organ: A novel site for prolactin action

“…To determine the size of the delayed rectifier K + current before and after PRL application, perforated‐cell voltage‐clamp experiments were performed in the presence of 500 nmol L ‐1 tetrodotoxin (TTX) in the external solution to block voltage‐gated Na + current. Previous research from our laboratory suggests that blocking Ca 2+ conductance does not alter the magnitude or properties of K + currents and such Ca 2+ conductance was not blocked in our voltage‐clamp experiments. Delayed rectifier K + current was isolated via a voltage‐step protocol requiring the neurone to be held at −75 mV for 100 ms, stepped up to −40 mV for 100 ms, then, for 250 ms, stepped from −80 mV to +20 mV in 10 mV increments.…”

Regulation of the T‐type Ca2+ channel Cav3.2 by hydrogen sulfide: emerging controversies concerning the role of H2S in nociception

“…Ion channels (specifically NMDA receptors; Abe & Kimura, ) were amongst the first family of cellular proteins recognized as being molecular targets of H 2 S. Since then, reports of ion channel regulation by H 2 S have grown rapidly (Peers et al . ; Kuksis & Ferguson, ; Zhang et al . ), as indicated by Fig.…”