Transient Receptor Potential Canonical Type 1 (TRPC1) Operates as a Sarcoplasmic Reticulum Calcium Leak Channel in Skeletal Muscle

Abstract

Extensive studies performed in nonexcitable cells and expression systems have shown that type 1 transient receptor potential canonical (TRPC1) channels operate mainly in plasma membranes and open through phospholipase C-dependent processes, membrane stretch, or depletion of Ca 2؉ stores. In skeletal muscle, it is proposed that TRPC1 channels are involved in plasmalemmal Ca 2؉ influx and stimulated by store depletion or membrane stretch, but direct evidence for TRPC1 sarcolemmal channel activity is not available. We investigated here the functional role of TRPC1 using an overexpressing strategy in adult mouse muscle fibers. Immunostaining for endogenous TRPC1 revealed a striated expression pattern that matched sarcoplasmic reticulum ( Transient receptor potential canonical 1 (TRPC1) 2 proteins consist of nonselective cation channels expressed in a great variety of multicellular organisms (1, 2). Extensive studies performed in nonexcitable cells or involving heterologously expressed channels have shown that TRPC1 channels operate mainly in homo-or heteromeric association with other TRPC isoforms as Ca 2ϩ -permeable channels in the plasma membrane. Parameters that control TRPC1 channel opening remain controversial. TRPC1 channels could be activated by direct interaction with endoplasmic reticulum inositol trisphosphate receptors or at least through phospholipase C-dependent processes, membrane stretch, or depletion of intracellular Ca 2ϩ stores (3). Much less data are available concerning endogenous TRPC1 channels in excitable cells. In skeletal muscle, TRPC1 proteins were first shown to be expressed in the sarcolemma of muscles from dystrophin-deficient mouse (mdx), a murine model of Duchenne muscular dystrophy, and were proposed to mediate a sarcolemmal store-operated Ca 2ϩ influx in adult fibers (4) and contribute to cell migration and fusion in cultured myoblasts as store-operated or stretch-activated channels (5, 6). Gervásio et al. (7) confirmed the sarcolemmal localization of TRPC1 in mouse muscle and indicated that the sarcolemmal level of TRPC1 was slightly increased in mdx fibers. Stiber et al. (8) also described a sarcolemmal pattern of expression associated with a striated transversal pattern assumed to correspond to costamers at the level of Z discs. TRPC1 was also found to associate with skeletal muscle scaffolding proteins, including caveolin-3 and Homer1 in adult muscle fibers and dystrophin and ␣1-syntrophin in cultured myotubes (7-9).Taken together, these data suggest that skeletal muscle TRPC1 channels are involved in sarcolemmal Ca 2ϩ influx possibly stimulated by store depletion or membrane stretch, but direct evidence for the existence of a measurable Ca 2ϩ conductance supported by TRPC1 channels at resting potentials is not available. We previously showed in adult mouse muscle fibers that sarcoplasmic reticulum (SR) Ca 2ϩ depletion failed to induce any increase in the resting whole-cell conductance and inward single channel activity (10). We also demonstrated that the resting and store-operat...

TRPC Channels As Effectors of Cardiac Hypertrophy

“…22 TRPC channels can also localize to membranes of other cellular compartments, such as the Golgi apparatus 23 or the ER/SR reticulum. 24 Consistent with such a localization, a role as a Ca 2ϩ leak channel in skeletal muscle SR has been attributed to TRPC1. 24 In the Golgi apparatus, the ankyrin domain in TRPC6 interacts with the ring finger protein RNF24 to cause organelle retention of TRPC6 and a putative role in protein secretion events.…”

“…24 Consistent with such a localization, a role as a Ca 2ϩ leak channel in skeletal muscle SR has been attributed to TRPC1. 24 In the Golgi apparatus, the ankyrin domain in TRPC6 interacts with the ring finger protein RNF24 to cause organelle retention of TRPC6 and a putative role in protein secretion events. 25 Vesicular trafficking and associated protein interactions might also modulate TRPC channel gating such as through the characterized association between the vesicle associated protein VAMP2 (vesicle-associated membrane protein 2) and the N terminus of TRPC3.…”

IL-1α Reversibly Inhibits Skeletal Muscle Ryanodine Receptor. A Novel Mechanism for Critical Illness Myopathy?

“…The effects of IL-1 on SR Ca 21 release were almost instantaneous and reversible once IL-1 interacted with RyR1 in the skinned fiber assay. This is not in contrast to the long incubation times needed for intact fibers to exert the action of IL-1 on membrane integrity, as, in the skinned fiber, the sarcolemma had been permeabilized either chemically or mechanically and immediate diffusional access to the myoplasm established (25) (30). The fact that the SR Ca 21 retention index (24) increase and the spark frequency decrease upon IL-1 application were well reproduced by tetracaine, together with the finding that IL-1 coimmunoprecipitated with RyR1, but not with SERCA (Figure 4), clearly point toward RyR1 as the main target for this cytokine.…”

Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium

“…Although we observed little plasma membrane TRPC1 in the urothelium, this channel was abundantly expressed intracellularly in what may be the ER and/or Golgi. Interestingly, TRPC-4 or -5 can interact with TRPC1 to form a heteromer, which facilitates TRPC1 trafficking to the plasma membrane (7,48). Therefore, TRPC1, possibly in a complex with TRPC4, may traffic to the umbrella cell plasma membrane in response to stretch and once there may contribute to mechanotransduction.…”