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Getting personal: Endogenous adenosine receptor signaling in lymphoblastoid cell lines

J M Hillger1, C Diehl1, E van Spronsen1

  • 1Division of Medicinal Chemistry, LACDR, Leiden University, The Netherlands.

Biochemical Pharmacology
|June 15, 2016
PubMed

Insights

Genetic variations impact drug effectiveness, especially for G protein-coupled receptors (GPCRs). Personalized cell lines revealed individual differences in adenosine A2A receptor (A2AR) function, highlighting a new approach for studying drug response variations.

Area of Science:

  • Pharmacogenomics
  • Molecular Pharmacology
  • Cellular Biology

Background:

  • Genetic variations significantly influence individual drug responses, posing challenges in pharmacotherapy.
  • G protein-coupled receptors (GPCRs) are common drug targets, and their functional variants can alter drug efficacy.
  • A systematic approach to studying real-life genetic variations in GPCR function is lacking.

Purpose of the Study:

  • To investigate real-life genetic variations in GPCR function using personalized cell lines.
  • To showcase the utility of lymphoblastoid cell lines (LCLs) in studying personalized drug responses.
  • To analyze adenosine A2A receptor (A2AR) signaling variations within a family.

Main Methods:

  • Utilized lymphoblastoid cell lines (LCLs) from a family of four.
  • Employed a non-invasive, label-free cellular assay to measure A2AR signaling.
  • Performed genotype comparisons focusing on single nucleotide polymorphisms (SNPs).

Main Results:

  • Significant differences in the potency of a partial agonist were observed in one individual.
  • Genotype analysis identified variations in two intron SNPs, including rs2236624, linked to caffeine-related sleep disorders.
  • Demonstrated the suitability of LCLs as a model system for studying genetic influences on A2AR and other GPCR responses.

Conclusions:

  • Lymphoblastoid cell lines (LCLs) provide a viable model for studying genetic influences on G protein-coupled receptor (GPCR) drug responses.
  • Observed functional differences in adenosine A2A receptor (A2AR) signaling suggest potential genotype-specific drug effects.
  • Further validation is required to confirm genotype-specific effects on drug response.
Keywords:
Adenosine (PubChem CID: 60961)Adenosine A(2A) receptorBAY60-6583 (PubChem CID: 11717831)CCPA (PubChem CID: 123807)CGS21680 (PubChem CID: 3086599)Cl-IB-MECA (PubChem CID: 3035850)G protein-coupled receptorsIstradefylline (PubChem CID: 5311037)LUF5448 (PubChem CID: 69538223)Label-freeLymphoblastoid cell linesNECA (PubChem CID: 448222)Precision medicineSingle Nucleotide PolymorphismZM241385 (PubChem CID: 176407)

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