Role of T-type channels in vasomotor function: team player or chameleon?
Low-voltage-activated T-type calcium channels play an important role in regulating cellular excitability and are implicated in conditions, such as epilepsy and neuropathic pain. T-type channels, especially Cav3.1 and Cav3.2, are also expressed in the vasculature, although patch clamp studies of isolated vascular smooth muscle cells have in general failed to demonstrate these low-voltage-activated calcium currents. By contrast, the channels which are blocked by T-type channel antagonists are high-voltage activated but distinguishable from their L-type counterparts by their T-type biophysical properties and small negative shifts in activation and inactivation voltages. These changes in T-channel properties may result from vascular-specific expression of splice variants of Cav3 genes, particularly in exon 25/26 of the III-IV linker region. Recent physiological studies suggest that T-type channels make a small contribution to vascular tone at low intraluminal pressures, although the relevance of this contribution is unclear. By contrast, these channels play a larger role in vascular tone of small arterioles, which would be expected to function at lower intra-vascular pressures. Upregulation of T-type channel function following decrease in nitric oxide bioavailability and increase in oxidative stress, which occurs during cardiovascular disease, suggests that a more important role could be played by these channels in pathophysiological situations. The ability of T-type channels to be rapidly recruited to the plasma membrane, coupled with their subtype-specific localisation in signalling microdomains where they could modulate the function of calcium-dependent ion channels and pathways, provides a mechanism for rapid up- and downregulation of vasoconstriction. Future investigation into the molecules which govern these changes may illuminate novel targets for the treatment of conditions such as therapy-resistant hypertension and vasospasm.
Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, 0200, Australia.
Ivana Y-T
IY
Kuo
Lauren
L
Howitt
Shaun L
SL
Sandow
Alexandra
A
McFarlane
Pernille B
PB
Hansen
Caryl E
CE
Hill
D000595:Amino Acid Sequence; D000818:Animals; D020747:Calcium Channels, T-Type / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D020747:Calcium Channels, T-Type; D020033:Protein Isoforms