T-Type Ca 2+ Channels in Cerebral Arteries: Approaches, Hypotheses, and Speculation OSAMA F. HARRAZ, AND DONALD G. WELSH Department of Physiology & Pharmacology, Hotchkiss Brain and Libin Cardiovascular Research Institutes, University of Calgary, Calgary, AB, Canada Address for correspondence: Donald G. Welsh, Ph.D., Department of Physiology & Pharmacology, GAA-14, Health Research Innovation Center, 3280 Hospital Dr. N.W. Calgary, Alberta T2N-2Z6, Canada. E-mail: dwelsh@ucalgary.ca Received 5 December 2012; accepted 7 January 2013. ABSTRACT Cerebral blood flow is controlled by a network of resistance arteries that dilate and constrict to mechanical and chemical stimuli. Vasoactive stimuli influence arterial diameter through alterations in resting membrane potential and the influx of Ca 2+ through voltage- gated Ca 2+ channels. Historically, L-type Ca 2+ channels were thought to be solely expressed in cerebral arterial smooth muscle. Recent studies have, however, challenged this perspective, by providing evidence of T-type Ca 2+ channels in vascular tissues. This perspective piece will introduce T-type Ca 2+ channels, their electrophysiological properties, and potential roles in arterial tone development. We begin with a brief overview of Ca 2+ channels and a discussion of the approaches used to isolate this elusive conduc- tance. We will then speculate on how the two T-type Ca 2+ channels expressed in cerebral arterial smooth muscle might differentially influence arterial tone. This discovery of T-type Ca 2+ channels alters our traditional understanding of Ca 2+ dynamics in vascular tissue and fosters new avenues of research and insight into the basis of arterial tone development. Key words: voltage-gated Ca 2+ channels, Ca 2+ regulation, vascular smooth muscle cells Abbreviations used: BK Ca , large-conductance Ca 2+ -activated K + channel; Ca V , voltage-gated Ca 2+ channel; IC 50 , concentration that elicits 50% inhibition; PKA, protein kinase A; PKG, protein kinase G; RyR, ryanodine receptor; STOC, spontaneous transient outward K + current; TMEM16A, Ca 2+ -activated Cl - channel; TRPM4, transient receptor potential cation channel subfamily M member 4; TRPV4, transient receptor potential cation channel subfamily V member 4; 1 3.2 -/- , Ca V 3.2 knockout mice. Please cite this paper as: Harraz OF, Welsh DG. T-type Ca 2+ channels in cerebral arteries: approaches, hypotheses, and speculation. Microcirculation 20: 299–306, 2013. INTRODUCTION The cardiovascular system is comprised of a muscular pump and a distribution network of arteries, veins, and capillaries. Within this integrated system, it is the resistance arteries and their ability to change diameter that determine the magnitude and distri- bution of tissue blood flow [12,59]. Under dynamic conditions, tone within this vascular network is regulated by multiple stimuli including changes in tissue metabolism [21,46], neural activity [8,61], blood flow [18], and intravascular pressure [22,28]. These vasoactive stimuli influence arterial diameter by regulating the phosphorylation state of the myosin regulatory light chain. This phosphorylation step is in turn dynamically controlled by myosin light-chain kinase and phosphatase, key enzymes whose activities are linked, either directly or indirectly, to global changes in cytosolic [Ca 2+ ] [45,62]. VASCULAR VOLTAGE-GATED Ca 2+ CHANNELS In vascular smooth muscle, global cytosolic [Ca 2+ ] is primarily set by steady-state changes in resting membrane potential and the graded opening of voltage-gated Ca 2+ channels [27,44,66,67]. There are ten genes that encode for the mammalian family of voltage-gated Ca 2+ channels; their products are divided into three subfamilies that include (i) Ca V 1.x (L-type), (ii) Ca V 2.x (P/Q-, N-, R-types), and (iii) Ca V 3.x (T-type) [10]. Splice variants of Ca V 1.2 channels are typically thought to dominate Ca V channel expression in cerebral arterial smooth muscle [28,29,36,44]. Ca V 1.2 chan- nels are heteromultimeric protein complexes consisting of a single pore forming a 1 subunit coassociated with auxiliary subunits (b, a 2 d, and c). Although the ionic pore subunit is sufficient to allow Ca 2+ influx, the auxiliary subunits are indispensable for optimal surface expression, gating kinetics, and channel regulation [10]. The a 1 subunit contains four domains (I–IV), each of which is comprised of six trans- membrane segments. Domains are connected by intracellular loops (I–II, II–III, and III–IV) that are subject to splicing and protein kinase regulation [10]. The C- and N-termini are both intracellular and are responsible for conferring key properties such as Ca 2+ -dependent inactivation [56]. The accessory b subunit is also intracellular and linked to the I–II loop, whereas the c subunit is transmembranous in nature DOI:10.1111/micc.12038 Invited Review ª 2013 John Wiley & Sons Ltd 299