Functions of Heteromeric Association Between Adenosine and P2Y Receptors

Abstract

It is now well accepted that G protein-coupled receptors (GPCRs) can be directly associated, as either homo- or hetero-oligomers, to alter their functions. G protein-coupled purinergic receptors, classified as adenosine receptors, and P2Y receptors (ATP receptors) are also found to oligomerize each other to alter their pharmacology. Specifically, adenosine receptor of A1 subtype (A1R) is able to form a heteromeric complex with P2Y receptor of P2Y1 type (P2Y1R) either in heterologously transfected cells or in rat brain tissues, as demonstrated by coimmunoprecipitation or bioluminescence resonance energy transfer methods in addition to double immunocytochemistry. It is shown that the heteromerization between A1R and P2Y1R generates an adenosine receptor with P2Y-like agonistic pharmacology, i.e., a potent P2Y1R agonist, adenosine 5'-O-(2-thiodiphosphate), binds the A1R binding pocket of the A1R/P2Y1R complex and inhibits adenylyl cyclase activity via Gi/o protein. This hetero-oligomerization between adenosine receptor and P2Y receptor might be one of the mechanisms for the adenine nucleotide-mediated inhibition of neurotransmitter release. The oligomerization of purinergic receptors is thus considered as an important regulation system in the central nervous system.

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

“…It is noteworthy that these findings were largely confirmed in/ex vivo, where the authors studied rat brain cortex, hippocampus, and cerebellum as well as primary cultures of cortical neurons (Yoshioka et al, 2002). In a later review, it was speculated that this heteromerization between adenosine A 1 and P2Y 1 receptor might be one of the mechanisms for the adenine nucleotide-mediated inhibition of neurotransmitter release (Nakata et al, 2005). However, the fact that the ATP-mediated inhibition of neurotransmitter release is eliminated in slices from A 1 knock-out mice suggests that a direct action at A 1 receptors after rapid breakdown is another likely explanation (Masino et al, 2002).…”

Purinergic modulation of norepinephrine release and uptake in rat brain cortex: contribution of glial cells

“…An interaction between A 1 and P2Y 1 receptors may explain the attenuation of the ADP␤S inhibitory effect by DPCPX. This interaction may result from the formation of A 1 /P2Y 1 heterooligomers (Nakata et al 2005;Schicker et al 2009), which combine pharmacological properties of the A 1 and P2Y 1 receptors and have been shown to be expressed in the rat brain cortex, hippocampus, and cerebellum (Nakata et al 2005). In functional assays, activation of A 1 /P2Y 1 heterodimers by CPA or ADP␤S caused an inhibition of adenylyl cyclase activity, which was prevented by the A 1 receptor antagonist DPCPX but not by the P2Y 1 receptor antagonist MRS 2179 (Yoshioka and Nakata 2004).…”

“…This problem has been partially overcome by using agonists metabolically more stable and by blocking the A 1 receptors, the main adenosine receptors involved in the modulation of transmitter release in the brain (Fredholm et al 2005). Additionally, several P2Y and adenosine receptors such as P2Y 1 , P2Y 2 , P2Y 12 , P2Y 13 , A 1 , and A 2A receptors may interact physically, forming heterooligomers between them but also with NTPDase1 (Nakata et al 2005;Schicker et al 2009), or may interact functionally (Quintas et al 2009;Tonazzini et al 2007), both mechanisms contributing to confound even more the identification of individual P2Y receptor subtypes involved in the regulation of synaptic transmission.…”

Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory

“…Furthermore, the A 1 R-P 2 Y 1 R heteroreceptor complexes show an A 1 R with P 2 Y 1 R agonist like recognition [106]. Thus, the orthosteric binding sites in the receptor protomers of these complexes change their pharmacology and also recognize novel transmitters.…”