Hemichannels, NO also induces the activation of Cx37- and Cx40-based hemichannels. Interestingly, this operate also demonstrated that NO crosses the plasma membrane preferentially by means of connexin hemichannels (Figueroa et al., 2013), no less than, by means of these formed by Cx37, Cx40 or Cx43. On the other hand, the impact of NO on Panx-1-formed channels is controversial, considering the fact that NO has been located to activate or inhibit these channels and in both cases S-nitrosylation was proposed to become involved (Zhang et al., 2008; Lohman et al., 2012). The prospective relevance of NO-induced connexin hemichannel activation in neurovascular coupling is highlighted by the contribution of NO towards the ATP-elicited Ca2+ signal in astrocytes that described Li and collaborators (Li et al., 2003). These authors found that the release of Ca2+ from the intracellular shops initiated by ATP results in the activation of a NOdependent pathway of Ca2+ influx that plays an important function in the improve in [Ca2+ ]i plus the subsequent Ca2+ retailer refilling observed in this response. The NO-induced Ca2+ influx did not rely on the activation of cGMP production (Li et al., 2003), suggesting the involvement of S-nitrosylation. Interestingly, the Ca2+ influx activated by NO was sensitive to Cd2+ and 2-aminoethoxydiphenyl borate (2-APB; Li et al., 2003). Even though Cd2+ is thought to become a nonselective Ca2+ channel blocker and 2-APB is recognized as an IP3 R antagonist, both blockers have been shown to inhibit connexin hemichannels (Tao and Harris, 2007; Tang et al., 2009). Then, these results suggest that NO-dependent connexin hemichannel activation by S-nitrosylation may be involved, not just in ATP release, but in addition inside the Ca2+ signaling evoked by ATP in astrocytes, and consequently, inside the Ca2+ wave propagation observed within the neurovascular coupling (Figure 1), which can be constant with the recent report indicating that inhibition or deletion of eNOS blunted the astrocyte-mediated neurovascular couplingdependent vasodilation (Stobart et al., 2013). Furthermore, as connexin hemichannels mediate the intercellular transfer of NO (Figueroa et al., 2013) and Cx43 is preferentially expressed in astrocytic endfeet (Simard et al., 2003), Cx43-formed hemichannels may contribute towards the neuronal activation-induced vasodilation by directing the NO signaling toward parechymal arterioles (Figure 1). Also of connexins, NO signaling has also been shown to become involved within the control of TRPV4 and BK channel function. NO regulates negatively TRPV4 channelsby S-nitrosylation (Lee et al., 2011) and induces the opening of BK directly by S-nitrosylation or via the cGMPPKG pathway (Bolotina et al., 1994; Tanaka et al., 2000), which suggests that NO may regulate the astrocytic Ca2+ signaling at different levels and contribute towards the BK-mediated vasodilation (Figure 1). Even though opening and 2-(Dimethylamino)acetaldehyde Epigenetics regulation of connexin hemichannels will not be yet clear inside the context of astrocyte function in typical physiological conditions, these data recommend that Ca2+ mediated activation of NO production might be involved within the regulation from the astrocytic Ca2+ signal triggered in neurovascular coupling by means of activation of a Ca2+ influx or ATP release by means of Cx43-formed hemichannels. Nonetheless, the involvement of connexin hemichannels or Panx-1 channels inside the NO-dependent regulation from the neuronal activationinitiated Ca2+ and ATP signaling in astrocytes remains to be determined.CONCLUDING REMARKS Neurovascular coupling is actually a compl.
