Solute carrier (SLC) transporters are a large and diverse class of relatively understudied transmembrane proteins. Due to their critical role in cellular homeostasis, physiological processes and... Show moreSolute carrier (SLC) transporters are a large and diverse class of relatively understudied transmembrane proteins. Due to their critical role in cellular homeostasis, physiological processes and disease development, there is a great number of SLCs that have the potential to be viable drug targets for the treatment of disease. Robust assays are required to identify and characterize potential drugs for SLCs, which are often screened in vitro using cell-based or cell-free systems. Conventional assays either require the use of chemical labels, which i) can be invasive and compromise a cell’s physiology, ii) are based on end-point measurements, iii) use cell preparations and/or iv) do not allow screening of a large number of compounds. This thesis presents the development and application of novel label-free assays based on electrical impedance that allow the assessment of functional activity for three human SLCs: the dopamine transporter (DAT, SLC6A3), norepinephrine transporter (NET, SLC6A2) and excitatory amino acid transporters (EAAT, SLC1 family). With the ability to screen and characterize SLC inhibitors, these assays are a new addition to the ever-expanding toolbox for SLC transporters and could prove valuable in drug discovery programs for a wide range of diseases. Show less
The traditional medical treatment paradigm focuses on prescribing one drug to treat all patients with a specific disease or condition, so called ‘one-size-fits-all’. However, it has been shown... Show moreThe traditional medical treatment paradigm focuses on prescribing one drug to treat all patients with a specific disease or condition, so called ‘one-size-fits-all’. However, it has been shown increasingly that differences between persons, such as in lifestyle or genes, can change both the course of a disease and effect of a drug. In order to adapt medical treatment and drug development to that, a concept know as precision medicine, it is essential to study which and how genetic differences affect drug response. This thesis describes the study of the influences of genetic variation on a specific class of drug targets, the G protein-coupled receptors (GPCRs).Altogether a novel cellular approach towards studying genetic effects on GPCR function has been explored and detailed throughout this thesis. Several GPCRs and different types of genetic variations were investigated, demonstrating together that personal cell lines in combination with label-free technology are an appropriate tool to enable GPCR pharmacogenetic studies. Incorporating aspects such as genetic variation in drug targets, representative model systems and appropriate assay technology are important factors for advancing GPCR drug discovery. The data presented in this thesis contributes towards the progress of applying precision medicine concepts to this class of drug targets. Show less
