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@article{Schobesberger:2017:cvr/cvx074,
author = {Schobesberger, S and Wright, P and Tokar, S and Bhargava, A and Mansfield, C and Glukhov, AV and Poulet, C and Buzuk, A and Monszpart, A and Sikkel, M and Harding, SE and Nikolaev, VO and Lyon, AR and Gorelik, J},
doi = {cvr/cvx074},
journal = {Cardiovascular Research},
pages = {770--782},
title = {T-tubule remodelling disturbs localised β2-adrenergic signalling in rat ventricular myocyte during the progression of heart failure},
url = {http://dx.doi.org/10.1093/cvr/cvx074},
volume = {113},
year = {2017}
}

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TY  - JOUR
AB  - AimsCardiomyocyte β2-adrenergic receptor (β2AR) cyclic adenosine monophosphate (cAMP) signalling is regulated by the receptors’ subcellular location within transverse tubules (T-tubules), via interaction with structural and regulatory proteins, which form a signalosome. In chronic heart failure (HF), β2ARs redistribute from T-tubules to the cell surface, which disrupts functional signalosomes and leads to diffuse cAMP signalling. However, the functional consequences of structural changes upon β2AR-cAMP signalling during progression from hypertrophy to advanced HF are unknown.Methods and resultsRat left ventricular myocytes were isolated at 4-, 8-, and 16-week post-myocardial infarction (MI), β2ARs were stimulated either via whole-cell perfusion or locally through the nanopipette of the scanning ion conductance microscope. cAMP release was measured via a Förster Resonance Energy Transfer-based sensor Epac2-camps. Confocal imaging of di-8-ANNEPS-stained cells and immunoblotting were used to determine structural alterations. At 4-week post-MI, T-tubule regularity, density and junctophilin-2 (JPH2) expression were significantly decreased. The amplitude of local β2AR-mediated cAMP in T-tubules was reduced and cAMP diffused throughout the cytosol instead of being locally confined. This was accompanied by partial caveolin-3 (Cav-3) dissociation from the membrane. At 8-week post-MI, the β2AR-mediated cAMP response was observed at the T-tubules and the sarcolemma (crest). Finally, at 16-week post-MI, the whole cell β2AR-mediated cAMP signal was depressed due to adenylate cyclase dysfunction, while overall Cav-3 levels were significantly increased and a substantial portion of Cav-3 dissociated into the cytosol. Overexpression of JPH2 in failing cells in vitro or AAV9.SERCA2a gene therapy in vivo did not improve β2AR-mediated signal compartmentation or reduce cAMP diffusion.ConclusionAlthough changes in T-tubule structure
AU  - Schobesberger,S
AU  - Wright,P
AU  - Tokar,S
AU  - Bhargava,A
AU  - Mansfield,C
AU  - Glukhov,AV
AU  - Poulet,C
AU  - Buzuk,A
AU  - Monszpart,A
AU  - Sikkel,M
AU  - Harding,SE
AU  - Nikolaev,VO
AU  - Lyon,AR
AU  - Gorelik,J
DO  - cvr/cvx074
EP  - 782
PY  - 2017///
SN  - 0008-6363
SP  - 770
TI  - T-tubule remodelling disturbs localised β2-adrenergic signalling in rat ventricular myocyte during the progression of heart failure
T2  - Cardiovascular Research
UR  - http://dx.doi.org/10.1093/cvr/cvx074
UR  - http://hdl.handle.net/10044/1/46231
VL  - 113
ER  -

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