Mechanism of Targeting the a Kinase Anchoring Protein AKAP18δ To the Membrane

Hörner, Andreas; Goetz, Frank; Klussmann, Enno; Pohl, Peter

doi:10.1016/j.bpj.2009.12.305

Cited by 2 publications

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“…The other lipids in this mixture are cardiolipin and phosphatidylglycerol. They give rise to a negative surface potential (55). In the absence of cholesterol, P m was equal to 1.1 cm/s (Fig.…”

Section: Permeabilities At Planar Membranesmentioning

confidence: 94%

Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

Zocher

Spoel

Pohl

et al. 2013

Biophysical Journal

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The permeability of lipid membranes for metabolic molecules or drugs is routinely estimated from the solute's oil/water partition coefficient. However, the molecular determinants that modulate the permeability in different lipid compositions have remained unclear. Here, we combine scanning electrochemical microscopy and molecular-dynamics simulations to study the effect of cholesterol on membrane permeability, because cholesterol is abundant in all animal membranes. The permeability of membranes from natural lipid mixtures to both hydrophilic and hydrophobic solutes monotonously decreases with cholesterol concentration [Chol]. The same is true for hydrophilic solutes and planar bilayers composed of dioleoyl-phosphatidylcholine or dioleoyl-phosphatidyl-ethanolamine. However, these synthetic lipids give rise to a bell-shaped dependence of membrane permeability on [Chol] for very hydrophobic solutes. The simulations indicate that cholesterol does not affect the diffusion constant inside the membrane. Instead, local partition coefficients at the lipid headgroups and at the lipid tails are modulated oppositely by cholesterol, explaining the experimental findings. Structurally, these modulations are induced by looser packing at the lipid headgroups and tighter packing at the tails upon the addition of cholesterol.

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Section: Permeabilities At Planar Membranesmentioning

confidence: 94%

Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

Zocher

Spoel

Pohl

et al. 2013

Biophysical Journal

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“…As already mentioned in section 1.2, AKAPs are crucial for building up functional cAMP microdomains. They localise to subcellular membrane locations for example due to electrostatic attraction of positively charged amino acids to negatively charged membrane lipids (Horner et al, 2012) to bring together PKA, other kinases, PDEs and phosphates (Diviani et al, 2011;Mauban et al, 2009;Scott et al, 2013;Troger et al, 2012) (Figure 2). It is believed that AKAPs anchor PKA due to a tight protein-protein interaction between an amphipathic helix and the dimerization and docking domain of the PKA-R subunit (Wong and Scott, 2004).…”

Section: Mechanisms For Camp Compartmentation In the Heartmentioning

confidence: 99%

Local cAMP dynamics in the SERCA2a signalling complex

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3",5"-cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that regulates multiple physiological functions by acting in distinct subcellular microdomains. Over the last few years, several targeted biosensors have been developed and used in cell lines or neonatal cardiomyocytes to investigate the molecular mechanisms behind cAMP compartmentation. However, it is unclear whether such biosensors can be successfully used for expression in vivo, especially in the context of disease such as cardiac hypertrophy.Importantly, cAMP regulates cardiac function by acting in distinct subcellular microdomains which are independently regulated and confined from the bulk cytosol. Today, this phenomenon is a well accepted paradigm known as cAMP compartmentation. In the heart, one of these microdomains is believed to be located around the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a). SERCA2a is crucial for diastolic calcium (Ca 2+ ) reuptake and is negatively regulated by phospholamban (PLN). cAMP binding to PKA leads to increased PLN phosphorylation thereby relieving the inhibitory effect of PLN on SERCA2a.Interestingly, SERCA2a expression and activity are known to be downregulated during cardiac disease but cAMP dynamics in such microdomains and their alterations in cardiac disease such as hypertrophy are not well understood. Therefore, the first transgenic mouse model expressing a cardiac specific SERCA2a targeted fluorescence resonance energy transfer (FRET)-based cAMP sensor, namely Epac1-PLN, has been developed in this PhD study.Freshly isolated adult cardiomyocytes of the transgenic mouse line have been used to directly monitor cAMP with high temporal and spatial resolution within the SERCA2a microdomain. To understand the molecular mechanisms that confine the SERCA2a microdomain from the bulk cytosol, FRET results gained in Epac1-PLN cardiomyocytes were compared to those obtained in cardiomyocytes expressing the cytosolic cAMP FRET sensor Epac1-camps. In healthy cells, local cAMP levels in the SERCA2a microdomain after βadrenergic receptor (β-AR) stimulation were ~4-fold higher compared to the bulk cytosol, which was due to direct phosphodiesterase (PDE)-dependent receptor-microdomain communication. Under basal conditions (in the absence of β-AR stimulation) PDE3 and PDE4 were crucial for confining the SERCA2a microdomain from the cytosol. However, in cardiac hypertrophy induced by transverse aortic constriction, the local basal PDE4-mediated cAMP degradation was significantly diminished, while the cytosolic cAMP dynamics were altered only after β-AR stimulation. Strikingly, local cAMP degradation but not whole-cell changes in PDE activity in hypertrophy led to a dramatic loss of receptor-microdomain

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Mechanism of Targeting the a Kinase Anchoring Protein AKAP18δ To the Membrane

Cited by 2 publications

References 0 publications

Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes

Local cAMP dynamics in the SERCA2a signalling complex

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