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Review
. 2019 Dec 24;9(1):55.
doi: 10.3390/cells9010055.

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Guillermo Avila  1 , Juan A de la Rosa  1 , Adrián Monsalvo-Villegas  1 , María G Montiel-Jaen  1
Affiliations
Review

Ca2+ Channels Mediate Bidirectional Signaling between Sarcolemma and Sarcoplasmic Reticulum in Muscle Cells

Guillermo Avila et al. Cells. .

Abstract

The skeletal muscle and myocardial cells present highly specialized structures; for example, the close interaction between the sarcoplasmic reticulum (SR) and mitochondria-responsible for excitation-metabolism coupling-and the junction that connects the SR with T-tubules, critical for excitation-contraction (EC) coupling. The mechanisms that underlie EC coupling in these two cell types, however, are fundamentally distinct. They involve the differential expression of Ca2+ channel subtypes: CaV1.1 and RyR1 (skeletal), vs. CaV1.2 and RyR2 (cardiac). The CaV channels transform action potentials into elevations of cytosolic Ca2+, by activating RyRs and thus promoting SR Ca2+ release. The high levels of Ca2+, in turn, stimulate not only the contractile machinery but also the generation of mitochondrial reactive oxygen species (ROS). This forward signaling is reciprocally regulated by the following feedback mechanisms: Ca2+-dependent inactivation (of Ca2+ channels), the recruitment of Na+/Ca2+ exchanger activity, and oxidative changes in ion channels and transporters. Here, we summarize both well-established concepts and recent advances that have contributed to a better understanding of the molecular mechanisms involved in this bidirectional signaling.

Keywords: Ca2+ channel; Ca2+-induced Ca2+ release (CICR); contractility; dihydropyridine receptor (DHPR); excitation-contraction coupling; intracellular Ca2+; ryanodine receptor (RyR).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The voltage-gated Ca2+ channels (VGCCs) govern feedback mechanisms of the T-tubule-SR junction and, thereby, also influence the SR-mitochondria communication. The figure illustrates the principal bidirectional signaling pathways that operate in skeletal (A) and cardiac (B) muscle. In both cases, an action potential (AP) activates Ca2+ channels of the sarcolemma (CaV1.1 and CaV1.2), which promotes SR Ca2+ release via RyRs (RyR1 and RyR2), in a process known as EC coupling (orthograde signaling). The underlying mechanisms, however, are distinct. In the latter, the CaV1.2 to RyR2 communication consists in Ca2+-induced Ca2+ release (CICR), whereas in the former, the CaV1.1 channels directly activate RyR1s, thanks to a physical link (Ca2+ is not required, and, thereby, this phenomenon is also known as voltage-gated SR Ca2+ release, VGCR). The rise in [Ca2+]i activates the SERCA pump and the NCX, returning [Ca2+]i to baseline levels—with the aid of Ca2+-dependent inactivation of both RyRs and CaV1.2 (CDI). A small portion of Ca2+ ions permeates into the mitochondrion (MT), e.g., via the mitochondrial Ca2+ uniporter (MCU). Then, a symbiotic relationship between the SR and mitochondria occurs, because the calcium ions stimulate the synthesis of ATP, which is required for not only SERCA activity but also the cross-bridge cycle of contraction. In parallel, the tricarboxylic acid (TCA) cycle generates reducing equivalents (e.g., NADH) which are transferred to the electron transport chain (complexes I–IV), whose activity produces superoxide ion (O−, dashed black line) which, in turn, is converted into H2O2. The latter is a substrate for the Fenton reaction (forming hydroxyl radical, OH-). These reactive oxygen species (ROS) can react with (and modulate) the EC-coupling related proteins (red lines), creating a delicate balance that contributes to optimal muscle performance. Nevertheless, an excessive rate of ROS generation can lead to severe oxidative damage, EC uncoupling, and cell death.
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