Interactions between dihydropyridine receptors and ryanodine receptors in striated muscle

Abstract

Excitation-contraction coupling in both skeletal and cardiac muscle depends on structural and functional interactions between the voltage-sensing dihydropyridine receptor L-type Ca(2+) channels in the surface/transverse tubular membrane and ryanodine receptor Ca(2+) release channels in the sarcoplasmic reticulum membrane. The channels are targeted to either side of a narrow junctional gap that separates the external and internal membrane systems and are arranged so that bi-directional structural and functional coupling can occur between the proteins. There is strong evidence for a physical interaction between the two types of channel protein in skeletal muscle. This evidence is derived from studies of excitation-contraction coupling in intact myocytes and from experiments in isolated systems where fragments of the dihydropyridine receptor can bind to the ryanodine receptors in sarcoplasmic reticulum vesicles or in lipid bilayers and alter channel activity. Although micro-regions that participate in the functional interactions have been identified in each protein, the role of these regions and the molecular nature of the protein-protein interaction remain unknown. The trigger for Ca(2+) release through ryanodine receptors in cardiac muscle is a Ca(2+) influx through the L-type Ca(2+) channel. The Ca(2+) entering through the surface membrane Ca(2+) channels flows directly onto underlying ryanodine receptors and activates the channels. This was thought to be a relatively simple system compared with that in skeletal muscle. However, complexities are emerging and evidence has now been obtained for a bi-directional physical coupling between the proteins in cardiac as well as skeletal muscle. The molecular nature of this coupling remains to be elucidated.

The recombinant dihydropyridine receptor II–III loop and partly structured ‘C’ region peptides modify cardiac ryanodine receptor activity

“…The strongly α-helical basic 'A' region peptide [21] also activates RyR1 with high affinity [10][11][12]20,22]. These functional interactions possibly reflect binding reactions that contribute to the protein-protein interactions in skeletal muscle [18,20]. The fact that the A peptides also interact with RyR2 provides evidence for potential DHPR-RyR interactions in the heart [13].…”

“…In addition, the corresponding fragments of the DHPR interact with RyR1 in vitro. The recombinant SDCL and the acidic C region [18] are high-affinity activators of RyR1 [12,[18][19][20]. The strongly α-helical basic 'A' region peptide [21] also activates RyR1 with high affinity [10][11][12]20,22].…”

Functional implications of modifying RyR‐activating peptides for membrane permeability

“…A 20 amino-acid peptide (peptide A), corresponding to a part of the loop between the second and third membrane-spanning segment of the skeletal dihydropyridine receptor (DHPR), is a part of a naturally occurring muscle protein and is a high-affinity activator of skeletal and cardiac RyR channels (El-Hayek et al, 1995;Dulhunty et al, 1999;Gurrola et al, 1999;Lamb et al, 2000;Stange et al, 2001;Dulhunty et al, 2002). Both the DHPR and the RyR are essential for skeletal muscle contraction (Tanabe et al, 1988).…”

Dihydropyridine Receptors Are Selective Markers of Th2 Cells and Can Be Targeted to Prevent Th2-Dependent Immunopathological Disorders

“…L-type calcium channels located at the plasma membrane are coupled, directly or not, to ryanodine receptors expressed at the surface of the endoplasmic reticulum and are implicated in the increase in [Ca 2ϩ ] i upon membrane depolarization (discussed in Ref. 28). DHPR have also been described in non excitable cells including pancreatic ␤ cells (29), renal epithelial cells (30), osteoblasts (31), erythroleukemia cells (32), B lymphocytes (15), NK cells (16), and dendritic cells (14).…”