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Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC.
Eur J Pharmacol. 2007 Oct 15; 572(1):32-9.EJ

Abstract

In the present study, we evaluated the effects of the synthetic cannabinoid receptor agonist (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212-2) and the active component of Cannabis delta-9-tetrahydrocannabinol (triangle up(9)-THC) on Na(+),K(+)-ATPase activity in synaptosomal mice brain preparation. Additionally, the potential exogenous cannabinoids and endogenous opioid peptides interaction as well as the role of G(i/o) proteins in mediating Na(+),K(+)-ATPase activation were also explored. The ouabain-sensitive Na(+),K(+)-ATPase activity was measured in whole-brain pure intact synaptosomes (obtained by Percoll gradient method) of female CF-1 mice and was calculated as the difference between the total and the ouabain (1 mM)-insensitive Na(+),K(+)-ATPase activities. Incubation in vitro of the synaptosomes with WIN55,212-2 (0.1 pM-10 microM) or triangle up(9)-THC (0.1 pM-0.1 microM), in a concentration-dependent manner, stimulated ouabain-sensitive Na(+),K(+)-ATPase activity. WIN55,212-2 was less potent but more efficacious than triangle up(9)-THC. N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (10 nM), a CB(1) cannabinoid receptor selective antagonist, had not effect per se but antagonized the enhancement of Na(+),K(+)-ATPase activity induced by both, WIN55,212-2 and triangle up(9)-THC. AM-251 produced a significant reduction in the E(max) of cannabinoid-induced increase in Na(+),K(+)-ATPase activity, but did not significantly modify their EC(50). On the other hand, co-incubation with naloxone (1 microM), an opioid receptor antagonist, did not significantly modify the effect of WIN55,212-2 and completely failed to modify the effect of triangle up(9)-THC on synaptosomal Na(+),K(+)-ATPase. Finally, pre-incubation with 0.5 microg of pertussis toxin (G(i/o) protein blocker) completely abolished the enhancement of ouabain-sensitive Na(+),K(+)-ATPase activity induced by WIN55,212-2. A lower dose, 0.25 microg, decreased the E(max) of WIN55,212-2 by 70% but did not significantly affect its EC(50). These results suggest that WIN55212-2 and triangle up(9)-THC indirectly enhance Na(+),K(+)-ATPase activity in the brain by activating cannabinoid CB(1) receptors in a naloxone-insensitive manner. In addition, the effect of WIN55,212-2 on neuronal Na(+),K(+)-ATPase is apparently due to activation of G(i/o) proteins.

Authors+Show Affiliations

Department of Pharmacy (Division of Molecular Pharmacology), Faculty of Chemistry, Pontificia Universidad Católica de Chile, Casilla 306, Santiago, 6094411, Chile.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17644088

Citation

Araya, Katherine A., et al. "Role of Cannabinoid CB1 Receptors and Gi/o Protein Activation in the Modulation of Synaptosomal Na+,K+-ATPase Activity By WIN55,212-2 and Delta(9)-THC." European Journal of Pharmacology, vol. 572, no. 1, 2007, pp. 32-9.
Araya KA, David Pessoa Mahana C, González LG. Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC. Eur J Pharmacol. 2007;572(1):32-9.
Araya, K. A., David Pessoa Mahana, C., & González, L. G. (2007). Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC. European Journal of Pharmacology, 572(1), 32-9.
Araya KA, David Pessoa Mahana C, González LG. Role of Cannabinoid CB1 Receptors and Gi/o Protein Activation in the Modulation of Synaptosomal Na+,K+-ATPase Activity By WIN55,212-2 and Delta(9)-THC. Eur J Pharmacol. 2007 Oct 15;572(1):32-9. PubMed PMID: 17644088.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC. AU - Araya,Katherine A, AU - David Pessoa Mahana,C, AU - González,Luis G, Y1 - 2007/06/21/ PY - 2007/01/10/received PY - 2007/05/29/revised PY - 2007/06/07/accepted PY - 2007/7/24/pubmed PY - 2007/12/8/medline PY - 2007/7/24/entrez SP - 32 EP - 9 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 572 IS - 1 N2 - In the present study, we evaluated the effects of the synthetic cannabinoid receptor agonist (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212-2) and the active component of Cannabis delta-9-tetrahydrocannabinol (triangle up(9)-THC) on Na(+),K(+)-ATPase activity in synaptosomal mice brain preparation. Additionally, the potential exogenous cannabinoids and endogenous opioid peptides interaction as well as the role of G(i/o) proteins in mediating Na(+),K(+)-ATPase activation were also explored. The ouabain-sensitive Na(+),K(+)-ATPase activity was measured in whole-brain pure intact synaptosomes (obtained by Percoll gradient method) of female CF-1 mice and was calculated as the difference between the total and the ouabain (1 mM)-insensitive Na(+),K(+)-ATPase activities. Incubation in vitro of the synaptosomes with WIN55,212-2 (0.1 pM-10 microM) or triangle up(9)-THC (0.1 pM-0.1 microM), in a concentration-dependent manner, stimulated ouabain-sensitive Na(+),K(+)-ATPase activity. WIN55,212-2 was less potent but more efficacious than triangle up(9)-THC. N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (10 nM), a CB(1) cannabinoid receptor selective antagonist, had not effect per se but antagonized the enhancement of Na(+),K(+)-ATPase activity induced by both, WIN55,212-2 and triangle up(9)-THC. AM-251 produced a significant reduction in the E(max) of cannabinoid-induced increase in Na(+),K(+)-ATPase activity, but did not significantly modify their EC(50). On the other hand, co-incubation with naloxone (1 microM), an opioid receptor antagonist, did not significantly modify the effect of WIN55,212-2 and completely failed to modify the effect of triangle up(9)-THC on synaptosomal Na(+),K(+)-ATPase. Finally, pre-incubation with 0.5 microg of pertussis toxin (G(i/o) protein blocker) completely abolished the enhancement of ouabain-sensitive Na(+),K(+)-ATPase activity induced by WIN55,212-2. A lower dose, 0.25 microg, decreased the E(max) of WIN55,212-2 by 70% but did not significantly affect its EC(50). These results suggest that WIN55212-2 and triangle up(9)-THC indirectly enhance Na(+),K(+)-ATPase activity in the brain by activating cannabinoid CB(1) receptors in a naloxone-insensitive manner. In addition, the effect of WIN55,212-2 on neuronal Na(+),K(+)-ATPase is apparently due to activation of G(i/o) proteins. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17644088/Role_of_cannabinoid_CB1_receptors_and_Gi/o_protein_activation_in_the_modulation_of_synaptosomal_Na+K+_ATPase_activity_by_WIN55212_2_and_delta_9__THC_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00715-7 DB - PRIME DP - Unbound Medicine ER -