Brief reviewRegulation of Ryanodine Receptors via Macromolecular Complexes: A Novel Role for Leucine/Isoleucine Zippers
Section snippets
FKBP12.6 Regulates RyR2
In 1989, Marks et al. (1989) identified a 12-kDa protein, originally identified as a peptide KC7 that co-purifies with RyR1, that was subsequently shown to be the FK506 binding protein (FKBP12), a cytosolic receptor for the immunosuppressant drugs FK506 and rapamycin (Schreiber 1991). FKBP12 is expressed at high levels in all types of muscle (Jayaraman et al. 1992). FKBP12 and a highly homologous protein 12.6-kDa protein (FKBP12.6) are cis–trans peptidyl–prolyl isomerases that are members of
PKA Phosphorylation of RyR2 Dissociates FKBP12.6 from the Channel
The RyR2 macromolecular complex includes FKBP12.6, PKA and its targeting protein mAKAP, PP1 and its targeting protein spinophilin, and PP2A with its targeting protein PR130 Marx et al. 2000, Marx et al. 2001b. Binding of FKBP12.6 to RyR2 is physiologically regulated by PKA phosphorylation of the channel that dissociates FKBP12.6 from RyR2 (Marx et al. 2000) resulting in increased activity (increased Po) of RyR2. Similarly, PKA phosphorylation of RyR1 also regulates FKBP12 binding (Marks et al.,
Acknowledgements
The authors thank members of the Marks laboratory for helpful discussions and comments on the manuscript. This work was supported by grante to A.R.M. from the NIH, the AHA, and the Richard and Lynne Kaiser Family Foundation, and the Whitaker Foundation (S.R.). A.R.M. is a Doris Duke Foundation Distinguished Clinical Scientist.
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2021, Tissue and CellCitation Excerpt :Blocking RyR immediately after SCI has been shown to be neuro-/axoprotective (Orem et al., 2017). RyRs are homotetrameric macromolecular protein complexes (Marks et al., 2002; Marx et al., 2000), whereby the calstabin subunit (FKBP12) is of particular interest because it stabilizes the channel in an state of reduced activity and as a result preventing a pathological release of calcium (Brillantes et al., 1994). Modifications of RyRs leading to a loss of calstabin from the channel macromolecular complex play an important role in neuropathology (Dridi et al., 2020; Lacampagne et al., 2017; Reiken et al., 2021).
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2018, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :Co-immunoprecipitation studies have revealed that the RyR macromolecular complex consists of (FKBP) calstabin, catalytic subunit of PKA (PKA), regulatory subunit of PKA (RII), protein phosphatases 1 (PP1) and 2A (PP2A), and an anchoring protein mAKAP [30]. Targeting of PKA, PP1, and PP2A to RyR is mediated by the binding of anchoring proteins to leucine/isoleucine zipper (LZ) motifs [31]. PP1 interaction with RyR2 is mediated by spinophilin binding to an LZ domain located between amino acids 530–704 [32].