Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms

Abstract

Dantrolene is an intra-cellularly acting skeletal muscle relaxant used for the treatment of the rare genetic disorder, malignant hyperthermia (MH). In most cases, MH susceptibility is caused by dysfunction of the skeletal ryanodine receptor (RyR1) harboring one of nearly 230 single-point MH mutations. The therapeutic effect of dantrolene is the result of a direct inhibitory action on the RyR1 channel, thus suppressing aberrant Ca2+ release from the sarcoplasmic reticulum. Despite the almost identical dantrolene-binding sequence exits in all three mammalian RyR isoforms, dantrolene appears to be an isoform-selective inhibitor. Whereas RyR1 and RyR3 channels are competent to bind dantrolene, the RyR2 channel, predominantly expressed in the heart, is unresponsive. However, a large body of evidence suggests that the RyR2 channel becomes sensitive to dantrolene-mediated inhibition under certain pathological conditions. Although a consistent picture of the dantrolene effect emerges from in vivo studies, in vitro results are often contradictory. Hence, our goal in this perspective is to provide the best possible clues to the molecular mechanism of dantrolene’s action on RyR isoforms by identifying and discussing potential sources of conflicting results, mainly coming from cell-free experiments. Moreover, we propose that, specifically in the case of the RyR2 channel, its phosphorylation could be implicated in acquiring the channel responsiveness to dantrolene inhibition, interpreting functional findings in the structural context.

ER stress increases expression of intracellular calcium channel RyR1 to modify Ca2+ homeostasis in pancreatic beta cells

“…To do so, we took advantage of the selective ER Ca 2+ channel antagonists xestospongin-C (XeC, 1 μM) ( 21 ) and dantrolene (Dan, 10 μM) ( 22 ), to block IP3Rs and RyR1, respectively. Dan mainly selectively inhibits RyR1 over RyR2 ( 22 , 23 , 24 ), but the selectivity remains controversial ( 25 ).…”

Synergistic Interaction of 5-HT1B and 5-HT2B Receptors in Cytoplasmic Ca2+ Regulation in Human Umbilical Vein Endothelial Cells: Possible Involvement in Pathologies

“…It has been shown that EC of the human mesenteric artery and immortalized EA.hy926 endothelial-derived cells express RyR3, whereas RyR1 and RyR2 were not detected in these cells [ 35 ]. RyR3 is known to be inhibited by dantrolene [ 36 ]. We used this compound to find out if RyRs in HUVEC are involved in the potentiation of the response to BW723C86 by CGS12066B.…”