Selma Anton’s scientific contributions

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Publications (1)


Figure 1.1 Two-dimensional scheme of a GPCR GPCRs are embedded in the lipid bilayer of cellular membranes and constitute of an extracellular amino-terminus, seven transmembrane spanning helices (TM1-7), an intracellular helix 8 and a carboxy terminus. TM1-7 are connected via three extracellular (ECL1-3) and three intracellular (ICL1-3) loops.
Figure 1.2 Conformational changes in GPCRs upon activation Crystal structures of three class A GPCRs depicted in the inactive and active conformation reveal a similar pronounced outward movement of TM6 (highlighted) involved in the activation process. β2AR-β2-adrenergic receptor, M2R-muscarinic acetylcholine receptor, µOR-µ-opioid receptor (image taken from [12] with permission from the American Chemical Society (ACS); further permission related to the material excerpted should be directed to the ACS https://pubs.acs.org/doi/full/10.1021/acs.chemrev.6b00177#showFigures)
Figure 1.3 G protein-cycle for a GPCR-G protein complex Agonist binding leads to the recruitment of the heterotrimeric G protein. GDP is released from the α-subunit upon formation of receptor-G protein complex. GTP binding results in dissociation of the α-and βγ-subunits from the receptor, upon which they can regulate their respective effector proteins (GS protein activates ACs through the α-subunit and Ca 2+ -channels through the βγ-subunits). The GS heterotrimer reassembles following hydrolysis of GTP to GDP within the α-subunit (extracted and modified from [8] with permission from Springer Nature; license number: 4564730845716).
Figure 1.4 General structure of arrestins The N-domain is depicted in black, the C-domain in grey. Loops are indicated in different colours, the residue numbers refer to bovine arrestin-1. The parts which are not resolved in the crystal structure are shown as dashed lines. The structure model is based on the crystal structure published by Hirsch et al. [58] (image taken from Scheerer and Sommer [57] with permission according to the creative commons license http://dx.doi.org/10.1016/j.sbi.2017.05.001)
Figure 1.5 GPCR regulation by β-arrestins After ligand binding, GRKs can phosphorylate specific receptor residues leading to β-arrestin recruitment. The GPCR-β-arrestin complex is internalized via clathrin-coated pits into intracellular compartments from where the receptor can signal, be degraded or get trafficked back to the membrane.

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Characterization of cAMP nanodomains surrounding the human Glucagon-like peptide 1 receptor using FRET-based reporters
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January 2021

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Selma Anton

Cyclic adenosine monophosphate (cAMP), the ubiquitous second messenger produced upon stimulation of GPCRs which couple to the stimulatory GS protein, orchestrates an array of physiological processes including cardiac function, neuronal plasticity, immune responses, cellular proliferation and apoptosis. By interacting with various effector proteins, among others protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac), it triggers signaling cascades for the cellular response. Although the functional outcomes of GSPCR-activation are very diverse depending on the extracellular stimulus, they are all mediated exclusively by this single second messenger. Thus, the question arises how specificity in such responses may be attained. A hypothesis to explain signaling specificity is that cellular signaling architecture, and thus precise operation of cAMP in space and time would appear to be essential to achieve signaling specificity. Compartments with elevated cAMP levels would allow specific signal relay from receptors to effectors within a micro- or nanometer range, setting the molecular basis for signaling specificity. Although the paradigm of signaling compartmentation gains continuous recognition and is thoroughly being investigated, the molecular composition of such compartments and how they are maintained remains to be elucidated. In addition, such compartments would require very restricted diffusion of cAMP, but all direct measurements have indicated that it can diffuse in cells almost freely. In this work, we present the identification and characterize of a cAMP signaling compartment at a GSPCR. We created a Förster resonance energy transfer (FRET)-based receptor-sensor conjugate, allowing us to study cAMP dynamics in direct vicinity of the human glucagone-like peptide 1 receptor (hGLP1R). Additional targeting of analogous sensors to the plasma membrane and the cytosol enables assessment of cAMP dynamics in different subcellular regions. We compare both basal and stimulated cAMP levels and study cAMP crosstalk of different receptors. With the design of novel receptor nanorulers up to 60nm in length, which allow mapping cAMP levels in nanometer distance from the hGLP1R, we identify a cAMP nanodomain surrounding it. Further, we show that phosphodiesterases (PDEs), the only enzymes known to degrade cAMP, are decisive in constraining cAMP diffusion into the cytosol thereby maintaining a cAMP gradient. Following the discovery of this nanodomain, we sought to investigate whether downstream effectors such as PKA are present and active within the domain, additionally studying the role of A-kinase anchoring proteins (AKAPs) in targeting PKA to the receptor compartment. We demonstrate that GLP1-produced cAMP signals translate into local nanodomain-restricted PKA phosphorylation and determine that AKAP-tethering is essential for nanodomain PKA. Taken together, our results provide evidence for the existence of a dynamic, receptor associated cAMP nanodomain and give prospect for which key proteins are likely to be involved in its formation. These conditions would allow cAMP to exert its function in a spatially and temporally restricted manner, setting the basis for a cell to achieve signaling specificity. Understanding the molecular mechanism of cAMP signaling would allow modulation and thus regulation of GPCR signaling, taking advantage of it for pharmacological treatment.

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