PMID- 23404999
OWN - NLM
STAT- MEDLINE
DCOM- 20131114
LR  - 20211021
IS  - 1755-3245 (Electronic)
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 98
IP  - 2
DP  - 2013 May 1
TI  - Cardiomyocyte ryanodine receptor degradation by chaperone-mediated autophagy.
PG  - 277-85
LID - 10.1093/cvr/cvt029 [doi]
AB  - AIMS: Chaperone-mediated autophagy (CMA) is a selective mechanism for the 
      degradation of soluble cytosolic proteins bearing the sequence KFERQ. These 
      proteins are targeted by chaperones and delivered to lysosomes where they are 
      translocated into the lysosomal lumen and degraded via the lysosome-associated 
      membrane protein type 2A (LAMP-2A). Mutations in LAMP2 that inhibit autophagy 
      result in Danon disease characterized by hypertrophic cardiomyopathy. The 
      ryanodine receptor type 2 (RyR2) plays a key role in cardiomyocyte 
      excitation-contraction and its dysfunction can lead to cardiac failure. Whether 
      RyR2 is degraded by CMA is unknown. METHODS AND RESULTS: To induce CMA, cultured 
      neonatal rat cardiomyocytes were treated with geldanamycin (GA) to promote 
      protein degradation through this pathway. GA increased LAMP-2A levels together 
      with its redistribution and colocalization with Hsc70 in the perinuclear region, 
      changes indicative of CMA activation. The inhibition of lysosomes but not 
      proteasomes prevented the loss of RyR2. The recovery of RyR2 content after 
      incubation with GA by siRNA targeting LAMP-2A suggests that RyR2 is degraded via 
      CMA. In silico analysis also revealed that the RyR2 sequence harbours six KFERQ 
      motifs which are required for the recognition Hsc70 and its degradation via CMA. 
      Our data suggest that presenilins are involved in RyR2 degradation by CMA. 
      CONCLUSION: These findings are consistent with a model in which oxidative damage 
      of the RyR2 targets it for turnover by presenilins and CMA, which could lead to 
      removal of damaged or leaky RyR2 channels.
FAU - Pedrozo, Zully
AU  - Pedrozo Z
AD  - Centro de Estudios Moleculares de la Celula, Facultad de Ciencias Quimicas y 
      Farmaceuticas & Facultad de Medicina, Universidad de Chile, Santiago 8380492, 
      Chile. zpedrozo@med.uchile.cl
FAU - Torrealba, Natalia
AU  - Torrealba N
FAU - Fernandez, Carolina
AU  - Fernandez C
FAU - Gatica, Damian
AU  - Gatica D
FAU - Toro, Barbra
AU  - Toro B
FAU - Quiroga, Clara
AU  - Quiroga C
FAU - Rodriguez, Andrea E
AU  - Rodriguez AE
FAU - Sanchez, Gina
AU  - Sanchez G
FAU - Gillette, Thomas G
AU  - Gillette TG
FAU - Hill, Joseph A
AU  - Hill JA
FAU - Donoso, Paulina
AU  - Donoso P
FAU - Lavandero, Sergio
AU  - Lavandero S
LA  - eng
GR  - R01 HL120732/HL/NHLBI NIH HHS/United States
GR  - HL-075173/HL/NHLBI NIH HHS/United States
GR  - HL-080144/HL/NHLBI NIH HHS/United States
GR  - HL-090842/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130211
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Benzoquinones)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Presenilins)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - Z3K3VJ16KU (geldanamycin)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - *Autophagy
MH  - Benzoquinones/pharmacology
MH  - Lactams, Macrocyclic/pharmacology
MH  - Lysosomes/metabolism
MH  - Molecular Chaperones/*physiology
MH  - Molecular Sequence Data
MH  - Myocardial Ischemia/metabolism
MH  - Myocytes, Cardiac/*metabolism
MH  - Oxidative Stress
MH  - Presenilins/physiology
MH  - Proteasome Endopeptidase Complex/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ryanodine Receptor Calcium Release Channel/chemistry/*metabolism
PMC - PMC3633160
EDAT- 2013/02/14 06:00
MHDA- 2013/11/15 06:00
PMCR- 2014/05/01
CRDT- 2013/02/14 06:00
PHST- 2013/02/14 06:00 [entrez]
PHST- 2013/02/14 06:00 [pubmed]
PHST- 2013/11/15 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - cvt029 [pii]
AID - 10.1093/cvr/cvt029 [doi]
PST - ppublish
SO  - Cardiovasc Res. 2013 May 1;98(2):277-85. doi: 10.1093/cvr/cvt029. Epub 2013 Feb 
      11.