Vascular smooth muscle store-operated Ca²⁺ channels: what a TRP!

Abstract

CALCIUM ENTRY TRIGGERED BY loss of Ca 2ϩ from endoplasmic reticulum Ca 2ϩ stores in vascular smooth muscle cells was first described by Casteels and Droogmans (6) 25 years ago. Subsequent studies have demonstrated that this is a ubiquitous process occurring in all eukaryotes from yeast to humans (see recent reviews for details: Refs. 4,21,31). However, the molecular identity of the ion channels that underlie storeoperated Ca 2ϩ (SOC) entry remains one of the significant unanswered questions in this important area of research. Compelling evidence has been presented that members of the canonical transient receptor potential family of channels, particularly TRPC1, are involved in SOC entry in vascular smooth muscle cells (5,11,28,33) and in other cell types (see Ref. 21 for numerous references). However, it is also clear that TRPC1 alone is unlikely to represent the SOC channel (SOCC) expressed in these cells (4,21). The study by Xu et al. (34) in this issue of the American Journal of Physiology, Heart and Circulatory Physiology, confirms and extends a preliminary report by this same group (35) that TRPC5 is another component of vascular smooth muscle SOCC. These findings are important for at least two reasons. First, the identity of an additional component of SOC entry in native vascular smooth muscle cells is a significant advance in our understanding of this important area of research. While TRP channels long have been implicated as SOCC, the characteristics of channels formed by individual TRP channel isoforms have poorly matched the characteristics of SOCC expressed in native cells. As demonstrated by Xu and colleagues (34, 35), the whole cell currents, ion selectivity, and pharmacology of SOCC in rabbit cerebral arteriolar smooth muscle cells nicely match heterologously expressed TRPC1/TRPC5 heteromultimers, strongly supporting a role for both TRPC isoforms in SOC entry in this system. However, it also should be noted that the hypothesis that TRPC1/TRPC5 heteromers represent at least a component of SOCC in native vascular smooth muscle cells has not been critically tested (see below).The second important contribution of the study by Xu et al. (34) is methodological. The use of the blocking antibody strategy to study the function of specific TRP channels, an approach championed by this group (5,(33)(34)(35), provides what appears to be a general strategy to dissect out the contribution of specific channel proteins involved in ionic currents and functional responses. While used successfully to demonstrate roles for TRPC1 and TRPC5 in SOC entry in vascular smooth muscle cells (5, 33-35), it should be recognized that this approach was first used as a tool to study voltage-gated K ϩ channels (38) and appears also to be effective in blockade of voltage-gated Na ϩ channels (35). Thus generation of antibodies directed at extracellular epitopes adjacent to the pore region of ion channels provides a means to study the specific function of a variety of ion channels and, importantly, the role played by distinct channel...

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…This finding further reinforces the direct relationship between TRPC channels and the activation of membrane-bound receptors. Given their downstream association with PLC activation and the presence of a CIRB-binding site, it has been long-proposed that TRPC channels open in response depletion of intracellular Ca 2+ stores, and thus would be the dominant source of store-operated Ca 2+ entry (SOCE) as well (47, 669, 756, 1240, 1263, 1525). However, TRPC channels lack the typical store-operated gating mechanisms present in other SOCE channel complexes (e.g., STIM1/Orai) (51, 328, 858).…”

Store‐operated calcium entry in vascular smooth muscle

“…STIM1 may interact with TRPC1 and is involved in SOCE ( Lopez et al , 2006 ). Jackson (2006) suggested that given the similarities between Ca 2+ handling in platelets and VSMCs, it is likely that STIM1 and possibly Orai1 as well take part in SOCE in VSMCs and human airway myocytes ( Jackson, 2006 ; Peel et al , 2006 ).…”

Increased caveolin‐1 expression enhances the receptor‐operated Ca2+ entry in the aorta of two‐kidney, one‐clip hypertensive rats

“…Accurate regulation of [Ca 2+ ] i in VSMCs is achieved primarily through voltage-dependent calcium channels (VDCCs) and nonvoltage-dependent calcium channels, such as store-operated Ca 2+entry channels (SOCCs) and receptor-operated Ca 2+ -entry channels (ROCCs) (Amberg & Navedo, 2013;Large, 2002;Taylor & Moneer, 2004). Both SOCCs and ROCCs are composed of multiple TRPC cation channel proteins (Earley, 2006;Jackson, 2006). The TRPC cation channels are a subtype of the TRP channel family (Clapham, Runnels, & Strubing, 2001;Earley & Brayden, 2015).…”