In signal transduction – as in business – location is key. In signal transduction – as in love – timing is everything. These adages are epitomized by neurotransmitter transporters, because (i) they must be delivered to the presynaptic specialization to accomplish their namesake action, i.e., the retrieval of released neurotransmitters from the synaptic cleft. (ii) They undergo a conformational cycle, the rates of which shape the time-dependent change in neurotransmitter concentration. We have been studying kinetic and spatial aspects of G protein-dependent signaling and of neurotransmitter transporters of the SLC6 (solute carrier-6) family for more than two decades.
Pharmacology is an opportunistic discipline: like physiology, biochemistry, molecular and cell biology, it is driven by a search for mechanistic understanding but with a purpose, i.e., to translate insights into a therapeutic principle. More than a decade ago we discovered by serendipity that ibogaine (an alkaloid from the African shrub Tabernanthe iboga) was an effective pharmacochaprone, i.e., it rescued folding-deficient mutants of the serotonin transporter (SERT/SLC6A4). Currently, the translational aspect of our work focuses on identifying compounds, which can rescue disease-associated mutants of folding-deficient SLC6 family members, in particular the dopamine transporter (DAT/SLC6A3) and the creatine transporter-1 (CRT1/SLC6A8). We also study how GPCR agonists can be combined to enhance hematopoietic stem cell transplantation.
- Zebedin-Brandl E, Themanns M, Kazemi Z, Nasrollahi-Shirazi S, Mussbacher M, Heyes E, Meissl K, Prchal-Murphy M, Strohmaier W, Krumpl G, Freissmuth M (2020) Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation. J Mol Med (Berl) 98:233-243. doi: 10.1007/s00109-019-01869-8.
- Nasrollahi-Shirazi S, Szöllösi D, Yang Q, Muratspahic E, El-Kasaby A, Sucic S, Stockner T, Nanoff C, Freissmuth M (2020) Functional impact of the G279S substitution in the adenosine A1-receptor (A1R-G279S), a mutation associated with Parkinson's disease. Mol Pharmacol 98:250–266. doi: 10.1124/molpharm.120.000003.
- Bhat S, Niello M, Pifl, C, Schicker K, Sitte HH, Freissmuth M, Sandtner W (2021) Handling of intracellular K determines voltage dependence of plasmalemmal monoamine transporter function. eLife 10:e67996. doi: 10.7554/eLife.67996
- Esendir E, Burtscher V, Coleman JA, Zhu R, Gouaux E, Freissmuth M, Sandtner W (2021) Extracellular loops of the serotonin transporter act as a selectivity filter for drug binding. J Biol Chem 297(1):100863. doi: 10.1016/j.jbc.2021.100863.
- Bhat S, Guthrie DA, Kasture A, El-Kasaby A, Cao J, Bonifazi A, Ku T, Giancola JB, Hummel T, Freissmuth M, Newman AH (2021) Tropane-based ibogaine analog rescues folding-deficient serotonin and dopamine transporters. ACS Pharmacol Transl Sci 4:503-516. doi: 10.1021/acsptsci.0c00102.
- Ponleitner M, Szöllösi D, El-Kasaby A, Koban F, Freissmuth M, Stockner T (2022) Thermal unfolding of the human serotonin transporter: differential effect by stabilizing and destabilizing mutations and cholesterol on thermodynamic and kinetic stability. Mol Pharmacol 101:95-105. doi: 10.1124/molpharm.121.000413.
- Farr CV, El-Kasaby A, Erdem FA, Sucic S, Freissmuth M, Sandtner W (2022) Cooperative binding of substrate and ions drives forward cycling of the human creatine transporter-1. Front Physiol 13:919439. doi: 10.3389/fphys.2022.919439.