Abstract:
:Phospholamban (PLN) is a key regulator of cardiac contraction and relaxation through its inhibition of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a). The inhibitory effect is attenuated upon protein kinase A (PKA) dependent phosphorylation of PLN. PLN exists in an equilibrium of pentamers and monomers. While monomers inhibit SERCA2a by direct interaction, the function of the pentamers is still unclear. Here, we tested the hypothesis that the PLN pentamer exhibits an important regulatory role by modifying PKA-dependent phosphorylation of inhibitory monomeric PLN subunits. Using Western blot analyses and antibodies specific for PKA-dependent phosphorylation of PLN, pentamers showed stronger signals than monomers both in transfected HEK293 cells and in cardiomyocytes. Upon activation of PKA, phosphorylation of protomers in the PLN pentamers increased faster and at lower levels of stimulation than PLN monomers, suggesting pentamers as the preferred PKA target. The comparison of phosphorylation patterns at different pentamer/monomer ratios revealed that pentamers delay phosphorylation of PLN monomers. A mechanistic explanation was provided by co-immunoprecipitation that suggested high affinity of PKA for PLN pentamers. Both monomers and pentamers were pulled down with SERCA2a indicating co-localization. Unlike pentamers, phosphorylated PLN monomers fully dissociated from the Ca(2+)-ATPase upon stimulation of PKA. These findings suggest a model where PLN pentamers reduce phosphorylation of monomers at baseline and delay monomer phosphorylation upon PKA stimulation leading to increased interaction of PLN monomers with SERCA2a.
journal_name
J Mol Cell Cardioljournal_title
Journal of molecular and cellular cardiologyauthors
Wittmann T,Lohse MJ,Schmitt JPdoi
10.1016/j.yjmcc.2014.12.020subject
Has Abstractpub_date
2015-03-01 00:00:00pages
90-7eissn
0022-2828issn
1095-8584pii
S0022-2828(14)00432-5journal_volume
80pub_type
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