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

Ion channels represent a large and growing family of target proteins regulated by gasotransmitters such as nitric oxide, carbon monoxide and, as described more recently, hydrogen sulfide. Indeed, many of the biological actions of these gases can be accounted for by their ability to modulate ion channel activity. Here, we report recent evidence that H₂S is a modulator of low voltage-activated T-type Ca²⁺ channels, and discriminates between the different subtypes of T-type Ca²⁺ channel in that it selectively modulates Cav3.2, whilst Cav3.1 and Cav3.3 are unaffected. At high concentrations, H₂S augments Cav3.2 currents, an observation which has led to the suggestion that H₂S exerts its pro-nociceptive effects via this channel, since Cav3.2 plays a central role in sensory nerve excitability. However, at more physiological concentrations, H₂S is seen to inhibit Cav3.2. This inhibitory action requires the presence of the redox-sensitive, extracellular region of the channel which is responsible for tonic metal ion binding and which particularly distinguishes this channel isoform from Cav3.1 and 3.3. Further studies indicate that H₂S may act in a novel manner to alter channel activity by potentiating the zinc sensitivity/affinity of this binding site. This review discusses the different reports of H₂S modulation of T-type Ca²⁺ channels, and how such varying effects may impact on nociception given the role of this channel in sensory activity. This subject remains controversial, and future studies are required before the impact of T-type Ca²⁺ channel modulation by H₂S might be exploited as a novel approach to pain management