Time-dependent differences of repeated administration with Δ9-tetrahydrocannabinol in proenkephalin and cannabinoid receptor gene expression and G-protein activation by μ-opioid and CB1-cannabinoid receptors in the caudate–putamen

1999 ◽  
Vol 67 (1) ◽  
pp. 148-157 ◽  
Author(s):  
Javier Corchero ◽  
Julian Romero ◽  
Fernando Berrendero ◽  
Javier Fernandez-Ruiz ◽  
José A. Ramos ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Receptor Gene ◽  
Repeated Administration ◽  
Time Dependent ◽  
Protein Activation ◽  
G Protein Activation ◽  
Receptor Gene Expression

scholarly journals Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

2014 ◽  
Vol 54 (1) ◽  
pp. 75-89 ◽  
Author(s):  
Pál Gyombolai ◽  
András D Tóth ◽  
Dániel Tímár ◽  
Gábor Turu ◽  
László Hunyady
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Double Mutant ◽  
Cannabinoid Receptor ◽  
Camp Accumulation ◽  
Protein Activation ◽  
Cb1 Cannabinoid Receptor ◽  
G Protein Activation ◽  
Dry Motif

The role of the highly conserved ‘DRY’ motif in the signaling of the CB1cannabinoid receptor (CB1R) was investigated by inducing single-, double-, and triple-alanine mutations into this site of the receptor. We found that the CB1R-R3.50A mutant displays a partial decrease in its ability to activate heterotrimeric Goproteins (∼80% of WT CB1R (CB1R-WT)). Moreover, this mutant showed an enhanced basal β-arrestin2 (β-arr2) recruitment. More strikingly, the double-mutant CB1R-D3.49A/R3.50A was biased toward β-arrs, as it gained a robustly increased β-arr1 and β-arr2 recruitment ability compared with the WT receptor, while its G-protein activation was decreased. In contrast, the double-mutant CB1R-R3.50A/Y3.51A proved to be G-protein-biased, as it was practically unable to recruit β-arrs in response to agonist stimulus, while still activating G-proteins, although at a reduced level (∼70% of CB1R-WT). Agonist-induced ERK1/2 activation of the CB1R mutants showed a good correlation with their β-arr recruitment ability but not with their G-protein activation or inhibition of cAMP accumulation. Our results suggest that G-protein activation and β-arr binding of the CB1R are mediated by distinct receptor conformations, and the conserved ‘DRY’ motif plays different roles in the stabilization of these conformations, thus mediating both G-protein- and β-arr-mediated functions of CB1R.

scholarly journals Implication of the Endocannabinoid System in the Locomotor Hyperactivity Associated with Congenital Hypothyroidism

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2657-2666 ◽  
Author(s):  
Teresa Asúa ◽  
Ainhoa Bilbao ◽  
Miguel Angel Gorriti ◽  
Jose Antonio Lopez-Moreno ◽  
Maria del Mar Álvarez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Cannabinoid Receptor ◽  
Receptor Gene ◽  
Hormone Replacement ◽  
Adult Life ◽  
Endocannabinoid System ◽  
Cb1 Receptor ◽  
Hormone Deficiency ◽  
Receptor Gene Expression

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB1) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB1 receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB1 receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

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