Succinate modulates Ca(2+) transient and cardiomyocyte viability through PKA-dependent pathway.
GPR91 is an orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate, a citric acid cycle intermediate, in several tissues. In the heart, the role of succinate is unknown. We now report that rat ventricular cardiomyocytes express GPR91. We found that succinate, through GPR91, increases the amplitude and the rate of decline of global Ca(2+) transient, by increasing the phosphorylation levels of ryanodine receptor and phospholamban, two well known Ca(2+) handling proteins. The effects of succinate on Ca(2+) transient were abolished by pre-treatment with adenylyl cyclase and cAMP-dependent protein kinase (PKA) inhibitors. Direct PKA activation by succinate was further confirmed using a FRET-based A-kinase activity reporter. Additionally, succinate decreases cardiomyocyte viability through a caspase-3 activation pathway, effect also prevented by PKA inhibition. Taken together, these observations show that succinate acts as a signaling molecule in cardiomyocytes, modulating global Ca(2+) transient and cell viability through a PKA-dependent pathway.
Aguiar
Carla J
CJ
Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte CEP, Brazil.
Andrade
Vanessa L
VL
Gomes
Enéas R M
ER
Alves
Márcia N M
MN
Ladeira
Marina S
MS
Pinheiro
Ana Cristina N
AC
Gomes
Dawidson A
DA
Almeida
Alvair P
AP
Goes
Alfredo M
AM
Resende
Rodrigo R
RR
Guatimosim
Silvia
S
Leite
M Fatima
MF
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D019802:Succinic Acid / Q000494:pharmacology*; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D019837:Ryanodine Receptor Calcium Release Channel; D019802:Succinic Acid; D000099211:Phospholamban; C523503:Sucnr1 protein, rat