Faculty Collaboration Database

Species dependence of A₃ adenosine receptor pharmacology and function. Purinergic Signal 2023 Sep;19(3):523-550

Date

12/21/2022

Pubmed ID

36538251

Pubmed Central ID

PMC9763816

DOI

10.1007/s11302-022-09910-1

Scopus ID

2-s2.0-85173914165 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

Efforts to fully understand pharmacological differences between G protein-coupled receptor (GPCR) species homologues are generally not pursued in detail during the drug development process. To date, many GPCRs that have been successfully targeted are relatively well-conserved across species in amino acid sequence and display minimal variability of biological effects. However, the A₃ adenosine receptor (AR), an exciting drug target for a multitude of diseases associated with tissue injury, ischemia, and inflammation, displays as little as 70% sequence identity among mammalian species (e.g., rodent vs. primate) commonly used in drug development. Consequently, the pharmacological properties of synthetic A₃AR ligands vary widely, not only in binding affinity, selectivity, and signaling efficacy, but to the extent that some function as agonists in some species and antagonists in others. Numerous heterocyclic antagonists that have nM affinity at the human A₃AR are inactive or weakly active at the rat and mouse A₃ARs. Positive allosteric modulators, including the imidazo [4,5-c]quinolin-4-amine derivative LUF6000, are only active at human and some larger animal species that have been evaluated (rabbit and dog), but not rodents. A₃AR agonists evoke systemic degranulation of rodent, but not human mast cells. The rat A₃AR undergoes desensitization faster than the human A₃AR, but the human homologue can be completely re-sensitized and recycled back to the cell surface. Thus, comprehensive pharmacological evaluation and awareness of potential A₃AR species differences are critical in studies to further understand the basic biological functions of this unique AR subtype. Recombinant A₃ARs from eight different species have been pharmacologically characterized thus far. In this review, we describe in detail current knowledge of species differences in genetic identity, G protein-coupling, receptor regulation, and both orthosteric and allosteric A₃AR pharmacology.

Author List

Gao ZG, Auchampach JA, Jacobson KA

Author

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Dogs
Humans
Mammals
Mast Cells
Mice
Protein Binding
Rabbits
Rats
Receptor, Adenosine A3
Signal Transduction