Biochemical and Functional Interplay Between Ion Channels and the Components of the Dystrophin-Associated Glycoprotein Complex

Abstract

Dystrophin is a cytoskeleton-linked membrane protein that binds to a larger multiprotein assembly called the dystrophin-associated glycoprotein complex (DGC). The deficiency of dystrophin or the components of the DGC results in the loss of connection between the cytoskeleton and the extracellular matrix with significant pathophysiological implications in skeletal and cardiac muscle as well as in the nervous system. Although the DGC plays an important role in maintaining membrane stability, it can also be considered as a versatile and flexible molecular complex that contribute to the cellular organization and dynamics of a variety of proteins at specific locations in the plasma membrane. This review deals with the role of the DGC in transmembrane signaling by forming supramolecular assemblies for regulating ion channel localization and activity. These interactions are relevant for cell homeostasis, and its alterations may play a significant role in the etiology and pathogenesis of various disorders affecting muscle and nerve function.

Free intramuscular Mg2+ concentration calculated using both 31P and 1H NMRS‐based pH in the skeletal muscle of Duchenne muscular dystrophy patients

“…The finding of a significantly lower free Mg 2+ content in dystrophic muscle should be seen in the light of the interaction with Ca 2+ , Na + and K + ion channels, which are known to be tightly linked to the dystrophin‐associated protein complex, and that the absence of dystrophin leads to an abnormal activity of these ion channels. Decreased amounts of total magnesium and increased total calcium and sodium levels have been found in skeletal muscle of DMD patients.…”

The Dystrophin Node as Integrator of Cytoskeletal Organization, Lateral Force Transmission, Fiber Stability and Cellular Signaling in Skeletal Muscle

“…The cell biological concept that the dystrophin-glycoprotein complex occupies central position at the fiber periphery is summarized in Figure 2. The diagram shows th the dystrophin-associated surface complex forms an organizing node that is majorly i volved in (i) the provision of sarcolemmal membrane integrity via a stabilizing linka between the intracellular actin cytoskeleton and the extracellular matrix protein lamin [11,13], (ii) the establishment of a molecular scaffold and anchoring system for ion cha nels and enzymes to mediate cellular signaling processes [60,61] (iii) the organization actin filament attachment and its associated cytoskeletal network [62,63], and (iv) the m diation of lateral force transmission from sarcomeric contraction to the endomysium a its connected layers of the extracellular matrix [64,65]. The upper panels summarize the main functions of the trans-sarcolemmal axis formed by the intracellular actin cytoskeleton, the dystrophin-dystroglycan complex, the basal lamina component laminin and the extracellular matrix.…”

“…This finding linked dystrophin with cellular signaling processes and was followed by a large number of detailed studies into the physiological and cell biological role of the dystrophin complex. The signaling and regulatory function of the dystrophin complexome in skeletal muscle was shown to involve key physiological players of the muscle plasmalemma, such as channels for potassium, sodium, calcium and water [60]. This includes especially interactions between alpha-syntrophin and inward rectifier K + -channels (K ir 2.1 at the neuromuscular junction) [155], Na + -channels (Na v 1.4 and Na v 1.5) [93], nonspecific channels of the transient receptor potential cation channel family (TRPC1 and TRPC4) [156], and the aquaporin water channel (AQ4) [157,158].…”

Sarcoglycan A mutation in miniature dachshund dogs causes limb-girdle muscular dystrophy 2D

“…Further sub-classification of LGMDs is based on an alphabetical system following the order of discovery of their genetic loci. The sarcoglycan complex is part of the dystrophin-glycoprotein complex, composed of four heavily glycosylated glycoproteins (α, β, γ, and δ-sarcoglycan) which help maintain sarcolemmal integrity [3]. Disorders (also termed sarcoglycanopathies) resulting from mutated genes encoding the sarcoglycansarcospan complex disrupt sarcolemmal integrity and cause LGMD types 2C-2F, respectively.…”