Physiological and Pathological Relevance of Selective and Nonselective Ca2+ Channels in Skeletal and Cardiac Muscle

Abstract

Contraction of the striated muscle is fundamental for human existence. The action of voluntary skeletal muscle enables activities such as breathing, establishing body posture, and diverse body movements. Additionally, highly precise motion empowers communication, artistic expression, and other activities that define everyday human life. The involuntary contraction of striated muscle is the core function of the heart and is essential for blood flow. Several ion channels are important in the transduction of action potentials to cytosolic Ca²⁺ signals that enable muscle contraction; however, other ion channels are involved in the progression of muscle pathologies that can impair normal life or threaten it. This chapter describes types of selective and nonselective Ca²⁺ permeable ion channels expressed in the striated muscle, their participation in different aspects of muscle excitation and contraction, and their relevance to the progression of some pathological states.

Keywords: Calcium; Dystrophy; Hypertrophy; Malignant hyperthermia; Orai1; Resting Ca2+ entry; Ryanodine receptor; STIM1; Store-operated Ca2+ entry; TRPC; Voltage-gated calcium channel.

Figure 1.

Cartoon showing the main Ca²⁺ fluxes in muscle cells. Primary and secondary active transport mechanisms in the plasma membrane, plasma membrane Ca²⁺ ATPase (PMCA) and Na⁺/Ca²⁺ exchanger (NCX), extrude Ca²⁺ from the cytosol against its electrochemical gradient and are coupled to ATP hydrolysis or the influx of Na⁺ down its electrochemical gradient, respectively. PMCA and NCX are important for keeping the resting Ca²⁺ concentration in quiescent cells or reestablishing resting Ca²⁺ levels after channel activation. Ca²⁺ permeability in the plasma membrane is low at rest (leak channels), but ion channels in the plasma membrane can open in response to stimuli, including voltage-gated channels and other channels such as store-operated channels, stretch-activated channels, and channels activated by signaling molecules (all grouped in “other channels”). When Ca²⁺ permeable channels open, Ca²⁺ enters the cells down its electrochemical gradient. Sarco-endoplasmic reticulum Ca²⁺ ATPase (SERCA) is expressed in the membrane of the SR; it is a Ca²⁺ ATPase that concentrates Ca²⁺ in the SR lumen. Intracellular ion channels expressed in the SR membrane such as the ryanodine receptor (RyR) can open enabling Ca²⁺ efflux from the SR lumen down its chemical gradient.

Figure 2.

Structural organization of the membranous system in skeletal muscle and the disposition of the Ca_V1.1 and RyR1 channels in the t-tubule and junctional SR membranes, respectively. A. Drawing depicting the disposition of the membranous system with respect to the contractile machinery in amphibian muscle. Note that the t-tubule (TT) runs along the side of the Z-disk (ZD). Mammalian skeletal muscle has a similar disposition, but the t-tubule runs along between the A and I bands (AI) having two t-tubules per sarcomere. Drawing reproduced with publisher permission from Peachey, 1965 [35]. B. Thin section of a triad visualized using electron microscopy. The t-tubule (TT) is clearly observed as surrounded by two terminal cisternae (TC) of the SR. Two densities between the junctional SR membrane and the t-tubule membrane are identifiable (2 per junction, 4 in total). Each density is a “foot” that corresponds to the large cytoplasmic domain of the RyR1. It has been proposed that two rows of RyR1 run along each junctional SR. Image reproduced with publisher permission from Franzini-Armstrong, 1970 [55]. C. Freeze fracture and rotary shadowing experiments were used to visualize the Ca_V1.1 particles along the longitudinal axis of the t-tubule. A group of four Ca_V1.1 particles is a tetrad; the image depicts 4 tetrads. In addition, a hypothetical array of RyR1s was overlayed considering the dimensions from CryoEM reconstructions. The best approximation for Ca_V1.1/RyR1 disposition in vivo is shown. Image reproduced with publisher permission from Paolini, Protasi and Franzini-Armstrong 2004 [58].

Figure 3.

Comparison between skeletal and cardiac EC coupling. The current model for skeletal type EC coupling hypothesizes physical communication between the L-type Ca²⁺ channel (Ca_V1.1, orange) and the RyR1 (blue) expressed in the t-tubule (TT) and sarcoplasmic reticulum (SR) membranes, respectively. The effective communication between Ca_V1.1 and the RyR1 requires two essential accessory proteins β_1a and Stac3. Other proteins are expressed in the junctional regions and may modulate skeletal EC coupling and some are relevant in skeletal muscle diseases (see [179]). In cardiac EC coupling, it is believed that Ca_V1.2 does not physically interact with the RyR2, but rather that clusters of these proteins are placed next to each other. Thus, a discrete group of Ca_V1.2 can activate a nearby cluster of RyR2 through a Ca²⁺-induced Ca²⁺ release mechanism.

Figure 4.

Na⁺ and Ca²⁺ dysregulation can contribute to maladaptive changes in striated muscle pathologies. In several pathological models of striated muscle, upregulation or gain on function of some ion channels not activated by voltage (e.g., TRPC, STIM/Orai) can promote Ca²⁺ and Na⁺ dysregulation. Alterations in the homeostasis of these ions may influence downstream signaling pathways, metabolic changes, and oxidative stress that can contribute to the final pathological phenotype.