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Be still my beating heart
FORUM
Be still my beating heart Marx, S.O. et al. (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (Ryanodine receptor): defective regulation in failing hearts. Cell 101, 365-376 both human and animal models, Ibynheart failure is broadly characterized a hyperadrenergic state and high levels of circulating catecholamines. However, downregulation and desensitization of b-adrenergic receptors in failing heart muscles has also been documented. Somewhat paradoxically, b-adrenergic blockers have proved to be important in the treatment of heart failure but, until recently, there was been little molecular basis to connect these observations. Marx et al. provide an exciting new advance in this field by showing that the tetrameric type 2 ryanodine receptor (RyR2) is unexpectedly hyperphosphorylated by protein kinase A (PKA) in failing heart muscle. This finding suggests that localized signaling events might indeed increase, rather than decrease, the phosphorylation of certain PKA substrates in cardiomyocytes from failing hearts. RyR2 is a tetrameric calcium channel that is known for its role in cardiac excitation–contraction (EC) coupling. It releases calcium ions (Ca21) from internal stores in the sarcoplasmic reticulum (SR) to trigger cardiac muscle contraction. Purified RyR2 channels are phosphorylated
by channel-associated PKA following co-immunoprecipitation from ventricular tissue. Using immunodetection, the authors established that this macromolecular complex also includes FKBP12.6, the protein phosphatases PP1 and PP2A, and the muscle A kinase anchoring protein (mAKAP). Most importantly, a direct connection to heart failure was made by comparing immune complexes from normal hearts with those from failing hearts, using back-phosphorylation of RyR2 with [g32P]ATP, as well as immunodetection of RyR2 with antiphosphoserine antibodies. These experiments show that in failing hearts three of the four PKA phosphorylation sites on the tetrameric RyR2 channel are phosphorylated, as compared with only one such site in normal hearts. Phosphorylation of RyR2 by PKA induces the dissociation of FKBP12.6 and causes severe defects in the operation of this crucial Ca21 channel. Specifically, phosphorylated RyR2 channels are susceptible to subconductance states and show increased sensitivity to Ca21-dependent activation, thus promoting the open state of the channel at inappropriately low
concentrations of intracellular Ca21. These defects might lead to depletion of Ca21 in the SR – the release of Ca21 is required for systolic muscle contraction. An important implication in the regulation of calcium flux in cardiomyocytes is provided by the anchoring of FKBP12.6, PKA, PP1 and PP2A to the RyR2 complex. Given that upstream components of the b-adrenergic cascade are localized to the T tubule–SR junction, it is now clear that phosphorylation and dephosphorylation of RyR2 can be regulated locally at the site of EC coupling. Marx et al. extend this idea by showing significant decreases in RyR2-associated PP1 and PP2A in failing hearts, which suggests that RyR2 hyperphosphorylation is due to diminished phosphatase activity in the receptor complex. Such regulated colocalization allows for PKA hyperphosphorylation even in the context of b-adrenergic desensitization, thus providing some rationale for the efficacy of b-blockers in treating heart failure. PKA-hyperphosphorylated channels with conductance defects in failing hearts provide a novel insight into the molecular physiology of cardiac dysfunction.
Commentary
Paul A. Clemons Dept of Chemistry and Chemical Biology, Box 29, 12 Oxford Street, Harvard University, Cambridge, MA 02138, USA. (E-mail: [email protected])
Trends Competition Winners We ran a competition for six months asking people to comment on their favourite Trends journal. We are now very pleased to announce the winners of the competition, which closed 30 June 2000. All winners won a 2-year subscription to a Trends journal of their choice. Duan Guangquan, Dept Biological Sciences, Yunnan University, China Dmytro Demydenko, Biological Research Center, Hungary Hakan Hedman, Umea University, Sweden Kwong Joo Leck, Australian National University, Australia Siegmund Wolf, Germany Todd Rosen, USA Simon Ladds, UK Jonathan Weitzman, France Anthony Attama, University of Nigeria, Nigeria Alberto Davila, DBBM/Instituto Oswaldo Cruz, Brazil Astrid Bunse, Bochum, Germany Valerie Hay, Montreal, Canada Andreas Kuhn, University of Hohenheim, Germany Congratulations to all these winners, we hope they enjoy benefiting from their Trends journals.
TIBTECH OCTOBER 2000 (Vol. 18)
0167-7799/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(00)01490-6
407
Be still my beating heart Marx, S.O. et al. (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (Ryanodine receptor): defective regulation in failing hearts. Cell 101, 365-376 both human and animal models, Ibynheart failure is broadly characterized a hyperadrenergic state and high levels of circulating catecholamines. However, downregulation and desensitization of b-adrenergic receptors in failing heart muscles has also been documented. Somewhat paradoxically, b-adrenergic blockers have proved to be important in the treatment of heart failure but, until recently, there was been little molecular basis to connect these observations. Marx et al. provide an exciting new advance in this field by showing that the tetrameric type 2 ryanodine receptor (RyR2) is unexpectedly hyperphosphorylated by protein kinase A (PKA) in failing heart muscle. This finding suggests that localized signaling events might indeed increase, rather than decrease, the phosphorylation of certain PKA substrates in cardiomyocytes from failing hearts. RyR2 is a tetrameric calcium channel that is known for its role in cardiac excitation–contraction (EC) coupling. It releases calcium ions (Ca21) from internal stores in the sarcoplasmic reticulum (SR) to trigger cardiac muscle contraction. Purified RyR2 channels are phosphorylated
by channel-associated PKA following co-immunoprecipitation from ventricular tissue. Using immunodetection, the authors established that this macromolecular complex also includes FKBP12.6, the protein phosphatases PP1 and PP2A, and the muscle A kinase anchoring protein (mAKAP). Most importantly, a direct connection to heart failure was made by comparing immune complexes from normal hearts with those from failing hearts, using back-phosphorylation of RyR2 with [g32P]ATP, as well as immunodetection of RyR2 with antiphosphoserine antibodies. These experiments show that in failing hearts three of the four PKA phosphorylation sites on the tetrameric RyR2 channel are phosphorylated, as compared with only one such site in normal hearts. Phosphorylation of RyR2 by PKA induces the dissociation of FKBP12.6 and causes severe defects in the operation of this crucial Ca21 channel. Specifically, phosphorylated RyR2 channels are susceptible to subconductance states and show increased sensitivity to Ca21-dependent activation, thus promoting the open state of the channel at inappropriately low
concentrations of intracellular Ca21. These defects might lead to depletion of Ca21 in the SR – the release of Ca21 is required for systolic muscle contraction. An important implication in the regulation of calcium flux in cardiomyocytes is provided by the anchoring of FKBP12.6, PKA, PP1 and PP2A to the RyR2 complex. Given that upstream components of the b-adrenergic cascade are localized to the T tubule–SR junction, it is now clear that phosphorylation and dephosphorylation of RyR2 can be regulated locally at the site of EC coupling. Marx et al. extend this idea by showing significant decreases in RyR2-associated PP1 and PP2A in failing hearts, which suggests that RyR2 hyperphosphorylation is due to diminished phosphatase activity in the receptor complex. Such regulated colocalization allows for PKA hyperphosphorylation even in the context of b-adrenergic desensitization, thus providing some rationale for the efficacy of b-blockers in treating heart failure. PKA-hyperphosphorylated channels with conductance defects in failing hearts provide a novel insight into the molecular physiology of cardiac dysfunction.
Commentary
Paul A. Clemons Dept of Chemistry and Chemical Biology, Box 29, 12 Oxford Street, Harvard University, Cambridge, MA 02138, USA. (E-mail: [email protected])
Trends Competition Winners We ran a competition for six months asking people to comment on their favourite Trends journal. We are now very pleased to announce the winners of the competition, which closed 30 June 2000. All winners won a 2-year subscription to a Trends journal of their choice. Duan Guangquan, Dept Biological Sciences, Yunnan University, China Dmytro Demydenko, Biological Research Center, Hungary Hakan Hedman, Umea University, Sweden Kwong Joo Leck, Australian National University, Australia Siegmund Wolf, Germany Todd Rosen, USA Simon Ladds, UK Jonathan Weitzman, France Anthony Attama, University of Nigeria, Nigeria Alberto Davila, DBBM/Instituto Oswaldo Cruz, Brazil Astrid Bunse, Bochum, Germany Valerie Hay, Montreal, Canada Andreas Kuhn, University of Hohenheim, Germany Congratulations to all these winners, we hope they enjoy benefiting from their Trends journals.
TIBTECH OCTOBER 2000 (Vol. 18)
0167-7799/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0167-7799(00)01490-6
407