Ryanodine receptor calcium channels and their partners as drug targets

doi:10.1016/j.bcp.2010.01.014

Biochemical Pharmacology

Volume 79, Issue 11, 1 June 2010, Pages 1535-1543

https://doi.org/10.1016/j.bcp.2010.01.014 Get rights and content

Abstract

Ryanodine receptors (RyRs) are high conductance intracellular cation channels that release calcium ions from stores such as the endoplasmic reticulum and sarcoplasmic reticulum. Although RyRs are expressed in many cell types, their roles have only been extensively characterised in tissues in which they are abundant: RyR1 is essential for excitation–contraction coupling in skeletal muscle; whereas RyR2 is required for the analogous signal transduction pathway in heart. Defects in RyR1 cause malignant hyperthermia and a spectrum of myopathies in skeletal muscle; whereas RyR2 dysregulation can result in fatal cardiac arrhythmias and is involved in heart failure. Altered RyR gating has been implicated in a range of other diseases, including epilepsy, neurodegeneration, pain and cancer. RyRs interact with a range of toxic substances, providing insights into their functional and structural properties. Consequently, these channel complexes represent potential therapeutic targets for treatment of numerous diseases. Furthermore, strategies for combating multicellular parasites and agricultural pests could exploit pharmacological differences between their RyRs and those of vertebrates. However, available pharmacological tools for manipulation of RyR gating are generally unsuitable for clinical, veterinary or agricultural use, owing to their lack of selectivity, inappropriate solubility in the aqueous or lipid environment, or generation of side-effects. The expression, subcellular distribution and gating of RyRs is modified by a wide variety of cellular proteins, some of which are expressed in a developmentally or tissue-restricted manner. This commentary examines the possibility of manipulating the expression and function of such proteins in order develop new drugs acting on RyR channel complexes.

Graphical abstract

Section snippets

Introduction: what are ryanodine receptors?

The ryanodine receptors (RyRs) are a family of high conductance cation channels that release Ca²⁺ from intracellular stores such as the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). Historically, research on these channels has centred on their roles in excitation–contraction (EC-) coupling in striated muscles, a process in which they play fundamental roles. Mammalian RyRs are encoded by three distinct genes, the products of which share ∼65% identity with one another and are

Diseases, drugs and commercial exploitation: which targets?

Ca²⁺ is a key second messenger, regulating numerous physiological and pathological processes [18]. RyRs show considerably larger conductances (∼100 pS for pCa²⁺) and longer open durations per opening event than most other cation channels, including their relatives and neighbours in the ER, the inositol 1,4,5-trisphosphate receptors (InsP₃Rs). Consequently RyRs release large quantities of Ca²⁺ per opening event (about 20-fold more per individual channel complex than InsP₃Rs) [3], indicating that

Which drugs act on RyR complexes?

Of the pharmacological reagents known to directly modulate RyR channel activity, only one, dantrolene, is routinely employed for manipulation of these channels under clinical circumstances (Table 1 ). Limitations of available drugs for therapeutic manipulation of RyR channels include: (1) low membrane permeability: RyRs are intracellular targets so drugs must be able to either diffuse across membranes, or be imported by cellular transporters, in order to act on these channel complexes; (2) low

RyR accessory proteins

The functional core of RyRs is a tetramer: these proteins do not act as channels in the monomeric state. Such complexes do not operate in isolation. In 1999, Mackrill first suggested that ‘…the functional properties of … RyRs within particular cells and subcellular domains are ‘customised’ by the accessory proteins present’[19]. This concept has been expanded to generate themes such as that of cells expressing a specific ‘Ca²⁺-toolkit’[18] that suits their function or underlies their

Regulation of RyR expression and subcellular localisation in disease

Certain proteins modulate RyR function via mechanisms distinct from acting as permanent, stoichiometrically associated components of these channel complexes: such proteins also represent targets for disease- or tissue-specific modulation of RyRs. For example, selenoprotein N1 is an ER/SR membrane protein, mutations in which can result in multi-minicore disease, a skeletal myopathy that also results from certain RYR1 mutations [60]. This protein binds to RyR complexes and modulates their gating

Future directions

Cellular proteins modulating gating, abundance or subcellular distribution of RyR complexes represent therapeutic targets of considerable potential. However, there are many issues surrounding the biology and pharmacology of these channels that must be resolved before this potential is fulfilled: (1) there is a need for systematic identification of RyR accessory proteins, and how these differ during development, between distinct tissues and during progression of disease; (2) information on how

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Citation Excerpt :
This suppression by Tet showed two phases: an initial inhibition during which cells showed responses similar to those caused by the vehicle alone, followed by a gradual rise in fura-2 ratio, whose peak was smaller than that in cells stimulated with 1 μM ryanodine alone. Dantrolene is a hydantion derivative that is a selective antagonist of RyRs [7]. Attempts to use this antagonist to inhibit Ca2+ increases stimulated by 1 μM Ry in Bewo cells were unsuccessful, since this reagent caused a rise in cellular autofluorescence at an excitation wavelength of 380 nm (even in the absence of fura-2), leading to an artefactual decrease in fura-2 ratio, (Supplemental Fig. 1A).
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^☆: Research in the author's laboratory is funded by grants RFP2007/BCIF165 and RFP2007/BMIF548 from Science Foundation Ireland. The author is grateful to Prof. John Challiss, University of Leicester, UK, for his advice during the preparation of this manuscript.

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CommentaryRyanodine receptor calcium channels and their partners as drug targets☆

Abstract

Graphical abstract

Section snippets

Introduction: what are ryanodine receptors?

Diseases, drugs and commercial exploitation: which targets?

Which drugs act on RyR complexes?

RyR accessory proteins

Regulation of RyR expression and subcellular localisation in disease

Future directions

Curr Opin Genet Dev

Trends Pharmacol Sci

J Biol Chem

J Biol Chem

Pharmacol Ther

Neuroscience

Brain Res Mol Brain Res

Lancet

J Biol Chem

J Biol Chem

J Biol Chem

Pharmacol Ther

J Am Coll Cardiol

FEBS Lett

Mayo Clin Proc

Heart Rhythm

Pestic Biochem Phys

Neurotoxicology

Pharmacol Ther

J Biol Chem

J Biol Chem

Am J Hum Genet

J Biol Chem

Second messenger function and the structure-activity relationship of cyclic adenosine diphosphoribose (cADPR)

FEBS J

Purification and reconstitution of the calcium release channel from skeletal muscle

Nature

Excitation–contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene

Nature

Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2

EMBO J

The ryanodine receptor/calcium channel genes are widely and differentially expressed in murine brain and peripheral tissues

J Cell Biol

Differential expression and regulation of ryanodine receptor and myo-inositol 1,4,5-trisphosphate receptor Ca2+ release channels in mammalian tissues and cell lines

Biochem J

Different involvement of type 1, 2, and 3 ryanodine receptors in memory processes

Learn Mem

A gene-specific cerebral types 1, 2, and 3 RyR protein knockdown induces an antidepressant-like effect in mice

J Neurochem

Comprehensive behavioral phenotyping of ryanodine receptor type 3 (RyR3) knockout mice: decreased social contact duration in two social interaction tests

Front Behav Neurosci

Up-regulation of the type 3 ryanodine receptor is neuroprotective in the TgCRND8 mouse model of Alzheimer's disease

J Neurochem.

Calcium signalling: dynamics, homeostasis and remodelling

Nat Rev Mol Cell Biol

Protein–protein interactions in intracellular Ca2+-release channel function

Biochem J

Molecular and clinical genetics of RyR1 disorders

Cyclic ADP-ribose induces a larger than normal calcium release in malignant hyperthermia-susceptible skeletal muscle fibers

Pflugers Arch

Commentary
Ryanodine receptor calcium channels and their partners as drug targets☆

Differential expression and regulation of ryanodine receptor and myo-inositol 1,4,5-trisphosphate receptor Ca²⁺ release channels in mammalian tissues and cell lines

Protein–protein interactions in intracellular Ca²⁺-release channel function