Striatal Adenosine A2A and Cannabinoid CB1 Receptors Form Functional Heteromeric Complexes that Mediate the Motor Effects of Cannabinoids

Abstract

The mechanism of action responsible for the motor depressant effects of cannabinoids, which operate through centrally expressed cannabinoid CB 1 receptors, is still a matter of debate. In the present study, we report that CB 1 and adenosine A 2A receptors form heteromeric complexes in co-transfected HEK-293T cells and rat striatum, where they colocalize in fibrilar structures. In a human neuroblastoma cell line, CB 1 receptor signaling was found to be completely dependent on A 2A receptor activation. Accordingly, blockade of A 2A receptors counteracted the motor depressant effects produced by the intrastriatal administration of a cannabinoid CB 1 receptor agonist. These biochemical and behavioral findings demonstrate that the profound motor effects of cannabinoids depend on physical and functional interactions between striatal A 2A and CB 1 receptors.

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

“…A 2A -CB 1 and A 2A -D 2 -CB 1 . There is one report on the heteromerization between A 2A and cannabinoid CB 1 receptors (Carriba et al, 2007). It was found that solubilized A 2A and CB 1 receptors coimmunoprecipitate from extracts of rat striatum, where they are colocalized in fibrillar structures.…”

An Update on Adenosine A2A-Dopamine D2 Receptor Interactions: Implications for the Function of G Protein-Coupled Receptors

“…A 1 receptor is widely distributed in the brain, including the striatum, while A 2A receptor is mostly concentrated in the striatum [2,3]. It is becoming increasingly obvious that the modulatory role of adenosine in the striatum is related to the ability of A 1 and A 2A receptors to heteromerize with themselves and with other GPCRs, such as dopamine, glutamate, cannabinoid and ATP receptors [4][5][6][7][8][9][10][11][12][13][14]. The present review focuses on the role of one particular adenosine receptor heteromer, the one constituted by the A 2A and the dopamine D 2 receptor, which is already having important implications for the treatment of neuropathologies involving the striatum (see below).…”

Wiring and firing neuronal networks: endocannabinoids take center stage

“…An increasingly accepted rule is that receptor homo-or heterodimers form functional units of GPCR signaling. The ability of opioid [41], A 2A adenosine [42], and D 2 dopamine receptors [43] to heteromerize with CB 1 Rs provides a mechanism to generate differential G-protein coupling at the CB 1 R, thus directly modulating physiological output. Alternatively, eCB signaling at CB 1 Rs can act as either upstream regulator (transactivation, BDNF/TrkB [25]) or downstream signal effector (N-cadherin/FGF-2 at FGF receptor [38,44]) thereby providing differential control of axonal growth and guidance.…”