T-type Calcium Channels in Arterial Smooth Muscle: Activity, Regulation and Function
Date
2015-03-30
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Abstract
Voltage-gated Ca2+ channels (CaV) are key regulators of excitation-contraction
coupling in arterial smooth muscle. Despite evidence of T-type CaV channels in rodent
smooth muscle, little is known of their regulation and function. This thesis sought to
delineate T-type Ca2+ channels, ascertain if they are regulatory targets of vasoactive
signaling pathways, and to reveal their function in arterial smooth muscle. Experiments
progressed from cells to whole animals, and employed an integrative range of techniques
such as electrophysiology, pressurized myography, intravascular catheterization,
polymerase chain reaction, western blotting and computational modeling. Using patch
clamp electrophysiology and defined pharmacology, T-type currents were successfully
separated from L-type, and further divided into components mediated by specific
subtypes (i.e. CaV3.1 and CaV3.2). In rat cerebral arteries, T-type channel activity was
shown to be a regulatory target of vasodilatory kinases. In particular, β-adrenergic
receptors and downstream activation of protein kinase A selectively inhibited CaV3.2
currents. Nitric oxide additionally suppressed CaV3 channels through protein kinase G
signaling. Subsequent work on rat and mouse arteries revealed an unanticipated function
for CaV3.2 in arterial tone development. In particular, we identified a novel feedback
response mediated by CaV3.2, whereby it triggered ryanodine receptors to release Ca2+
sparks that consequently activate the large conductance Ca2+-activated K+ channel to
hyperpolarize and relax arteries. While the majority of the experimental work was
conducted in animals, access to human brain tissues provided the opportunity to translate
our foundational observations. Indeed, human findings revealed for the first time the
presence of three distinct CaV subtypes in cerebral arterial smooth muscle and that each
subtype uniquely orchestrates arterial tone development and blood flow. In conclusion,
this thesis revises our knowledge on Ca2+ handling in arterial smooth muscle by
describing a novel paradigm in which T-type channels either facilitate or counteract
arterial tone development.
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Keywords
Physiology, Biophysics, Pharmacology
Citation
Harraz, O. F. (2015). T-type Calcium Channels in Arterial Smooth Muscle: Activity, Regulation and Function (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28530