Reciprocal dihydropyridine and ryanodine receptor interactions in skeletal muscle activation

Abstract

Dihydropyridine (DHPR) and ryanodine receptors (RyRs) are central to transduction of transverse (T) tubular membrane depolarisation initiated by surface action potentials into release of sarcoplasmic reticular (SR) Ca2+ in skeletal muscle excitation-contraction coupling. Electronmicroscopic methods demonstrate an orderly positioning of such tubular DHPRs relative to RyRs in the SR at triad junctions where their membranes come into close proximity. Biochemical and genetic studies associated expression of specific, DHPR and RyR, isoforms with the particular excitation-contraction coupling processes and related elementary Ca2+ release events found respectively in skeletal and cardiac muscle. Physiological studies of intramembrane charge movements potentially related to voltage triggering of Ca2+ release demonstrated a particular qγ charging species identifiable with DHPRs through its T-tubular localization, pharmacological properties, and steep voltage-dependence paralleling Ca2+ release. Its nonlinear kinetics implicated highly co-operative conformational events in its transitions in response to voltage change. The effects of DHPR and RyR agonists and antagonists upon this intramembrane charge in turn implicated reciprocal rather than merely unidirectional DHPR-RyR interactions in these complex reactions. Thus, following membrane potential depolarization, an orthograde qγ-DHPR-RyR signaling likely initiates conformational alterations in the RyR with which it makes contact. The latter changes could then retrogradely promote further qγ-DHPR transitions through reciprocal co-operative allosteric interactions between receptors. These would relieve the resting constraints on both further, delayed, nonlinear qγ-DHPR charge transfers and on RyR-mediated Ca2+ release. They would also explain the more rapid charging and recovery qγ transients following larger depolarizations and membrane potential repolarization to the resting level.

Multiple targets for flecainide action: implications for cardiac arrhythmogenesis

“…Flecainide may also act directly on SR RyR2‐Ca 2+ release channels, probably through open‐state block (Hilliard et al , ), with efficacies and potencies varying with channel activity (Savio‐Galimberti and Knollmann, ). Antagonism of open‐state RyR2 channels may be specific to flecainide in contrast to the prolonged RyR2 channel closure produced by tetracaine (Huang, ; Hilliard et al , ; Huang et al , ). Flecainide would then produce optimal antagonist actions in association with the increased activity of ‘leaky’ CPVT as opposed to WT RyR2 channels.…”

Knockdown of Death-Associated Protein Expression Induces Global Transcriptome Changes in Proliferating and Differentiating Muscle Satellite Cells

“…The CACNG1 gene encodes the dihydropyridine receptor (DHPR) gamma subunit, one of the five subunits of the L-type calcium channel (Rossi and Dirksen, 2006). The DHPR is located in the transverse tubule and associates with RYR1 to elicit calcium release from the SR into the sarcoplasm (Rossi and Dirksen, 2006;Huang et al, 2011). The gamma subunit of the DHPR, in particular, may act as a calcium antagonist during times of cell stress (Andronache et al, 2007).…”

Expanding Proteostasis by Membrane Trafficking Networks

“…Indeed, the flexibility of TPN-based TRaCKS suggests that the plethora of emerging "unconventional" pathways may have a common framework that simply reflects the versatility of TPN function-and, thus, may not be so unconventional. These now include, for example, the genesis of autophagic membranes from the ER (Gee et al 2011;Deretic et al 2012) and the identification of multiple unanticipated compartment linkages including ER-phagosome (Hubber and Roy 2010;Huang et al 2011), ER-mitochondrial (Friedman et al 2011;Westermann 2011), Golgi-cell surface (Golgi-bypass) (Nickel 2010; Grieve and Rabouille 2011), ER-peroxisome (Lam et al 2011;Dimitrov et al 2013), preGolgi -endosome (Saraste et al 2009), and intranuclear-cytoplasmic trafficking pathways (Montpetit and Weis 2012;Speese et al 2012). In this regard, Golgi structure/function relationships have been a particularly acute area of controversy with many models (Morre and Ovtracht 1977;Emr et al 2009;Papanikou and Glick 2009;Pfeffer 2010;Glick and Luini 2011;Mironov and Beznoussenko 2011;Munro 2011b).…”