Time line of Andrew R. Marks’ discovery of leaky ryanodine receptors (RyRs) and novel therapeutics that fix this leak

1989
Cloned RyR1/calcium release channel cDNA (PNAS 86:8683-8687).

1992
Identified FKBP12 (calstabin1) as a subunit of the RyR1 channel (JBC 267: 9474-9477).

1994
Functionally expressed recombinant RyR1 channels and demonstration that calstabin1 (FKBP12) stabilizes the closed state of the channel (i.e. prevents leak) (Cell 77: 513-523).

1998
Discovered that calstabin1 is required for coupled gating between RyR1 channels, removal of calstabin1 results in uncoupled channels that are leaky (Science 281:818-821).

2000
Discovered that RyR2 channels are leaky in failing hearts due to stress-induced loss of calstabin2 from the channel macromolecular complex (Cell 101:365-376).

2003
Discovered that depletion of calstabin2 results in leaky RyR2 channels that cause exercise-induced sudden cardiac death, RyR2 channel mutations in patients cause stress-induced sudden death (Cell 113:829-840).

2004
Demonstrated that a rycal small molecule prevents loss of calstabin2 from RyR2 channels and inhibits exercise induced arrhythmias and sudden cardiac death (Science 304:292-6).

2005
Demonstrated that a rycal prevents heart failure progression after myocardial infarction and improves skeletal muscle function (PNAS 102:9607-9612).

2005
Discovered that a phosphodiesterase in the RyR2 complex is required to prevent hyperphosphorylation of the channel, loss of calstabin2 and heart failure and arrhythmias (Cell 123:25-35).

2009
Discovered leaky RyR1 channels in Duchenne muscular dystrophy and demonstration that a rycal inhibits muscle damage and improves exercise capacity (Nature Medicine 15:325-330).

2010
Discovered that stress-induced nitrosylation/oxidation of RyR channels combined with PKA phosphorylation depletes channels of calstabin resulting in intracellular calcium leak that causes heart failure progression
(JCI 120: 4375-87 ; JCI 120: 4388-98).

2011
Discovered age-dependent oxidation of RyR1 in skeletal muscle that depletes RyR1 channels of calstabin1 resulting in intracellular SR calcium leak that causes mitochondrial calcium overload and age-dependent muscle weakness that can be prevented and/or reversed using an oral Rycal (S107) that inhibits leak through RyR channels. (Cell Metabolism 14:196-207)

2012
Discovered that stress-induced oxidation of RyR2 channels in hippocampal neurons depletes channels of calstabin resulting in cognitive dysfunction that can be prevented using a Rycal or genetically altered mice that harbor RyR2 channels that cannot be PKA phosphorylated. (Cell 150, 1055–1067, 2012)

2014
Discovered the high resolution structure of the RyR1 channel solved by single-particle electron cryomicroscopy at an overall resolution of 4.8A°. This structure elucidates the domains of the channel, the pore and provides a mechanism for calcium dependent gating of the channel.(Nature 2014 Dec 1. doi: 10.1038/nature13950. [Epub ahead of print])

2016
Using high-resolution cryo-EM structures discovered the mechanisms controlling the gating and activation of the RyR1 channel. This study provides the first detailed examination of the structural basis for controlling intracellular calcium release required to activation muscle contraction (Cell 167:145-157)

Columbia University | Vagelos College of Physicians and Surgeons