**Acknowledgements**

*Basic and Clinical Understanding of Microcirculation*

tility in health and disease [82, 84, 86, 93].

therefore the subject of future studies.

**5. Conclusions**

channels, multiple K+

**4.2 T-type Ca2+ channels**

stochastic and persistent activity of LTCCs was modulated by membrane potential [92]. However, the occurrence of LTCCs with persistent activity is limited to specific regions of the surface membrane and has been demonstrated to be highly dependent on PKC activity and AKAP5 expression [81, 86]. The activity of phosphatases, such as PP2B, that are targeted to the channel by AKAP5, counteracts anchored kinase activity and restricts persistent LTCC activity (**Figure 3**) [89]. Accordingly, in vascular smooth muscle in which PKC is inhibited or cells from mice with genetically depleted PKC or AKAP5, the frequency of persistent LTCC activity is minimal [86, 87, 93]. In addition, PP2B inhibition stimulates persistent LTCC events in cells from wild type but not AKAP5<sup>−</sup>/<sup>−</sup> mice, suggesting that removing this "brake" facilitates kinase-mediated potentiation of channel activity [86, 89]. These results suggest an important role for AKAP5-anchored PKC and PP2B activity in modulating basal persistent LTCC activity. The physiological significance of these findings is underscored by data indicating that persistent LTCC events account for 50% of the total dihydropyridine-sensitive (e.g., LTCCs) Ca2+ influx at physiological membrane potentials [92], which is critical for vascular smooth muscle contrac-

T-type Ca2+ channels are formed by pore-forming α1 subunits with similar topology as that of the LTCC α1c subunit, but with no known auxiliary subunits that modulate channel function [74]. TTCCs are activated at more hyperpolarized potentials and show similar conductance with Ca2+ or Ba2+ as charge carriers. Vascular smooth muscle cells express several TTCC α1 subunits, including CaV3.1 (α1G) and CaV3.2 (α1H) [9, 94–98]. Intriguingly, CaV3.1, which is found in murine vascular smooth muscle, seems to be replaced by CaV3.3 (α1I) in human cells [96], suggesting that expression of TTCC α1 subunits is species-dependent. TTCCs have been shown to contribute to vascular smooth muscle excitability in several vascular beds from different species [9, 98]. However, rigorous analysis revealed that different CaV3.X subunits may have very divergent physiological responses. For instance, whereas CaV3.1 (CaV3.3) mediates low-pressure-induced constriction, CaV3.2 contributes to the negative feedback regulation of vascular tone by stimulating the RyR/BKCa axis (**Figure 3**) [64, 95, 96]. TTCCs can also be regulated by signaling molecules. Indeed, the NO/PKG and AC/PKA axes both inhibit vascular TTCCs [99, 100], which may have key implications in vascular smooth muscle excitability. Whether these signaling molecules are organized and targeted by scaffold proteins such as AKAPs to areas near TTCCs to fine-tune their function is unclear and

Vascular smooth muscle excitability is exquisitely controlled by a repertoire of ion channels, which in themselves, are regulated by several vasoactive agents. The precise regulation of ion channels in vascular smooth muscle cells is essential for the dynamic adjustment of vascular tone necessary to maintain adequate tissue perfusion and blood pressure. Here, we have provided a brief overview of our current knowledge of key ion channels and their regulation by receptor-mediated signaling pathways that are activated by various vasoactive agents to modulate vascular smooth muscle excitability and therefore vascular tone. We focused on several TRP

sized ion channel regulation by signaling pathways associated with the Gs/AC/PKA,

channel subtypes, and various classes of VGCCs. We empha-

**12**

We thank the members of the Navedo Lab for critically reading early versions of the manuscript. This work was supported by NIH grants R01HL098200, R01HL121059 and R01HL149127 (to MFN), T32HL086350 (to AUS), and a UC Davis Academic Federation Innovative Development Award (to MN-C).
