Getting personal: Endogenous adenosine receptor signaling in lymphoblastoid cell lines.
Genetic differences between individuals that affect drug action form a challenge in drug therapy. Many drugs target G protein-coupled receptors (GPCRs), and a number of receptor variants have been noted to impact drug efficacy. This, however, has never been addressed in a systematic way, and, hence, we studied real-life genetic variation of receptor function in personalized cell lines. As a showcase we studied adenosine A2A receptor (A2AR) signaling in lymphoblastoid cell lines (LCLs) derived from a family of four from the Netherlands Twin Register (NTR), using a non-invasive label-free cellular assay. The potency of a partial agonist differed significantly for one individual. Genotype comparison revealed differences in two intron SNPs including rs2236624, which has been associated with caffeine-induced sleep disorders. While further validation is needed to confirm genotype-specific effects, this set-up clearly demonstrated that LCLs are a suitable model system to study genetic influences on A2AR response in particular and GPCR responses in general.
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
J M
JM
Hillger
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
C
C
Diehl
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
E
E
van Spronsen
Department of Biological Psychology, VU University Amsterdam, The Netherlands.
D I
DI
Boomsma
Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, The Netherlands.
P E
PE
Slagboom
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.
L H
LH
Heitman
Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands. Electronic address: ijzerman@lacdr.leidenuniv.nl.
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AP
IJzerman
D058917:Adenosine A2 Receptor Antagonists / Q000378:metabolism; D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D008024:Ligands; D008297:Male; D020641:Polymorphism, Single Nucleotide; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014430:Twins, Monozygotic / Q000235:genetics
D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D043705:Receptor, Adenosine A2A
Adenosine (PubChem CID: 60961); Adenosine A(2A) receptor; BAY60-6583 (PubChem CID: 11717831); CCPA (PubChem CID: 123807); CGS21680 (PubChem CID: 3086599); Cl-IB-MECA (PubChem CID: 3035850); G protein-coupled receptors; Istradefylline (PubChem CID: 5311037); LUF5448 (PubChem CID: 69538223); Label-free; Lymphoblastoid cell lines; NECA (PubChem CID: 448222); Precision medicine; Single Nucleotide Polymorphism; ZM241385 (PubChem CID: 176407)