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Research Group Molina
Aim
We focus on understanding the basic cellular pathomechanisms underlying cardiac diseases, with special attention on cardiac arrhythmias. In particular, we are interested in cyclic nucleotides signaling in human myocytes and how the remodeling on cAMP/cGMP-dependent kinases (such as PKA, and CaMKII via Epac) signaling is linked to compartment-specific changes in calcium handling.
Scope of Research
Cardiac arrhythmias • calcium handling • cAMP/cGMP signalling • GPCRs
Research Projects
Our aim is to clarify how specific molecular alterations in cardiac cells and disease-related remodelling cause electrical instability and generate arrhythmias and to apply this knowledge to develop new mechanism-based and patient-tailored therapeutic strategies.
1. Role of PDEs in cAMP dynamics and calcium handling in atrial fibrillation. We hypothesize that there are unifying regulatory mechanisms, such as the second messenger cAMP generated by GPCRs activation and its compartmentalized signalling via PDEs, underpinning pathological changes in electrical properties of the atria. The overall goal of this project is to determine the role of PDEs and GsPCR in the chronic AF associated remodelling of cellular calcium handling and atrial arrhythmogenesis.
2. Epac microdomain regulation of calcium handling via cAMP and CaMKII in atrial fibrillation. Our aim is to explore the localization and role of EPAC and CaMKII microdomains in human pathological atrial remodelling and arrhythmias.
3. Regional specific remodelling of cGMP pathway in human atrial fibrillation. Although it seems clear that cGMP regulates key proteins of excitation-contraction coupling, its functional role is still controversial and no studies have been performed to directly assess cGMP dynamics in human atrial myocytes. Our aim is to study the role of cGMP in atrial function and disease and to clarify to which extent cGMP-hydrolyzing phosphodiesterases (PDEs) regulate cGMP signaling in HAMs from patients in sinus rhythm (SR) and with AF.
ng-term study, we also assess whether pathological flow patterns in initially small aneurysms can predict future aneurysm growth.
4. Defining neurocardiac interactions in the human heart. In collaboration with Prof. David J. Paterson in Oxford we want to study which type of neurons reside in different cardiac chambers and how do these neurons interact with and affect cardiomyocytes in patho-physiological
conditions.
Key Techniques
- Cardiomyocytes, neurons and fibroblasts isolation
- Primary cell cultures, including human cells
- Fluorescence resonance energy transfer (FRET)
- Patch-clamp
- Measurement of ion currents
Measurement of action potentials - Contraction measurements
- Confocal calcium imaging
- Immunostaining and confocal microscopy
- Proximity ligation assays (PLA)
- qPCR
Group Members
Claudia Kass,
Administrative
David Revuelta,
PhD student
Andrea Brunetti,
PhD student
Johanna Bufler,
MD student
José Luís Delgado,
Research Lab Technician
Nefeli Grammatica-Pavlidou,
MD student
Franziska Reinhardt,
MD student
Publications
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Phosphodiesterase 8 governs cAMP/PKA-dependent reduction of L-type calcium current in human atrial fibrillation: a novel arrhythmogenic mechanism
Grammatika Pavlidou N, Dobrev S, Beneke K, Reinhardt F, Pecha S, Jacquet E, Abu-Taha IH, Schmidt C, Voigt N, Kamler M, Schnabel RB, Baczkó I, Garnier A, Reichenspurner H, Nikolaev VO, Dobrev D, Molina CE
Eur Heart J. 2023 Jul 14;44(27):2483-2494. doi: 10.1093/eurheartj/ehad086. -
Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling.
Reinhardt F*, Beneke K*, Grammatica Pavlidou N, Conradi L, Reichenspurner H, Hove-Madsen L, Molina CE.
Cells 2021 10(11), 3042. doi: 10.3390/cells10113042.
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Rise of cGMP by partial phosphodiesterase-3A degradation enhances cardioprotection during hypoxia.
Bork NI, Kuret A, Cruz Santos M, Molina CE, Reiterd B, Reichenspurner R, Friebee A, Skryabinf BV, Rozhdestvenskyf TS, Kuhne M,Lukowskic R, Nikolaev NO
Redox Biol. 2021 Nov 6;48:102179. doi: 10.1016/j.redox.2021.102179. -
ESC working group on cardiac cellular electrophysiology position paper: relevance, opportunities, and limitations of experimental models for cardiac electrophysiology research.
Odening KE, Gomez AM, Dobrev D, Fabritz L, Heinzel FR, Mangoni ME, Molina CE, Sacconi L, Smith G, Milan Stengl, Thomas D, Zaza A, Remme CA, Heijman J.
Europace 2021 Nov 8;23(11):1795-1814. doi: 10.1093/europace/euab142.. doi: 10.1093/europace/euab142 -
Mapping genetic changes in the cAMP-signaling cascade in human atria.
Garnier A, Bork NI, Jacquet E, Zipfel S, Muñoz-Guijosa C, Baczkó I, Reichenspurner H, Donzeau-Gouge P, Maier LS, Dobrev D, Girdauskas E, Nikolaev VO, Fischmeister R, Molina CE.
J Mol Cell Cardiol. 2021 Feb 22;155:10-20. doi: 10.1016/j.yjmcc.2021.02.006. -
Molecular Basis of Atrial Fibrillation Initiation and Maintenance.
Beneke K, Molina CE.
Hearts 2021 2(1), 170-187. doi: 10.3390/hearts2010014.
Grants/Awards
- Prof. Molina is funded by the Gertraud and Heinz Rose Foundation.
- 2024-2028:
Second messenger nanodomains in human atrial myocytes: from local signalling regulation to personalized therapeutic approaches | DFG | Heisenberg Programme - 2022-2025:
Mapping cAMP nanodomains in human atrial myocytes and their dysregulation in atrial fibrillation | DFG |
358’125 CHF - 2019-2022:
Role of PDE8 in cAMP dynamic and calcium signaling in atrial fibrillation | DFG |
494’200 CHF - 2019-2020:
Role of atrial metabolism dysfunction and cAMP remodeling in arrhythmogenesis in type 2 diabetes | DZHK Share Expertise |
43’156 CHF - 2013-2014:
Effects of atrial fibrillation on the distribution and frequency of spontaneous calcium release events in human atrial myocytes | Marie Curie Actions (PIEF)– European Commission|
166’336 CHF - 2011-2012:
Role of PDE4 on cAMP dynamics and calcium handling in atrial fibrillation | Institut de France |
104’000 CHF
Most important collaboration partners
- D. Paterson (University of Oxford): neuronal activation of cAMP signalling in human cells.
- M. Zaccolo (University of Oxford): cAMP compartmentalization in human HFpEF
- R. Fischmeister (INSERM, Paris): β-adrenergic signal transmission in the human heart.
- C. Dessauer (UTHealth, Houston): AC’s in the human atrium.
- D. Bers (UC Davis, California): CaMKII signals in the human atria.
- J. Heijman (University of Graz): Computational modelling of PDEs in atrial myocytes.