Voltage-gated Ca 2+ channels (Cav) are highly expressed in the adrenal chromaffin cells of mammalian species. Besides shaping action potential waveforms, they are directly involved in the excitation-secretion coupling underlying catecholamine release and, possibly, control other Ca 2+ -dependent events that originate near the membrane. These functions are shared by a number of Cav channel types (L, N, P/Q, R and T) which have different structure-function characteristics and whose degree of expression changes remarkably among mammalian species. Understanding precisely the functioning of each voltage-gated Ca 2+ channels is a crucial task that helps clarifying the Ca 2+ -dependent mechanisms controlling exocytosis during physiological and pathological conditions.In this paper, we focus on classical and new roles that L-and T-type channels play in the control of chromaffin cell excitability and neurotransmitter release. Interestingly, L-type channels are shown to be implicated in the spontaneous autorhythmicity of chromaffin cells, while T-type channels, which are absent in adult chromaffin cells, are coupled with secretion and can be recruited following long-term b-adrenergic stimulation or chronic hypoxia. This suggests that like other cells, adrenal chromaffin cells undergo effective remodelling of membrane ion channels and cell functioning during prolonged stress conditions.
The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicleinjected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0·5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected.Cannabinoid system: CB 1 receptors: Food intake: Nutritional value: WIN 55,212-2: AM 251: Serotonin: Acetic acid 5-hydroxy-indol: c-fos Expression Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. The endogenous cannabinoid system is involved in mechanisms that regulate energy metabolism, and interacts with many other signalling systems that play an important role in metabolic regulation (1) . The cannabinoid type 1 (CB 1 ) receptor has been strongly implicated in the regulation of food intake (2) . CB 1 receptors are present in the brain and in the periphery. In the brain, CB 1 receptors have been identified in pathways responsible for reward and energy balance (3 -5) , whereas in the periphery, CB 1 receptors have been identified in the gut (6 -8) , as well as in hepatocytes (9) and adipocytes (3,10) . CB 1 receptor agonists such as D 9 -tetrahydrocannabinol, together with the endocannabinoids, anandamide and 2-arachidonoylglycerol, increase food intake in both man and animals (11) . The enhancement of food intake can also be induced by other cannabinoid CB 1 receptor agonists such as WIN 55, . This action is blocked or reversed by the selective CB 1 receptor antagonist SR 141716A (13) and by the structurally and pharmacologically similar compound AM 251 (14,15) .Since the nutritive utilization of any foodstuff can be significantly affected by the amount of food consumed, we undertook the study of food intake regulation at the central and peripheral level using the CB 1 receptor agonist WIN 55,212-2 and the CB 1 inverse agonist AM 251 administered at different doses by means of intracerebroventricular (icv) or ...
a b s t r a c tUsing immortalized hypothalamic GT1-7 neurons, which express the CB1 cannabinoid receptor (CB1R) and three Ca 2+ channel types (T, R and L), we found that the CB1R agonist WIN 55,212-2 inhibited the voltage-gated Ca 2+ currents by about 35%. The inhibition by WIN 55,212-2 (10 M) was reversible and prevented by nifedipine (3 M), suggesting a selective action on L-type Ca 2+ channels (LTCCs). WIN 55,212-2 action exhibited all the features of voltage-independent Ca 2+ channel modulation: (1) no changes of the activation kinetics, (2) equal depressive action at all potentials and (3) no facilitation following strong prepulses. At variance with WIN 55,212-2, the CB1R inverse agonist AM-251 (10 M) caused 20% increase of Ca 2+ currents. The inhibition of LTCCs by WIN 55,212-2 was prevented by overnight PTX-incubation and by intracellular perfusion with GDP--S. The latter caused also a 20% Ca 2+ current up-regulation. WIN 55,212-2 action was also prevented by application of the PKA-blocker H89 or by loading the neurons with 8-CPT-cAMP. Our results suggest that LTCCs in GT1-7 neurons are partially inhibited at rest due to a constitutive CB1R activity removed by AM-251 and GDP--S. Activation of CB1R via PTX-sensitive G proteins and cAMP/PKA pathway selectively depresses LTCCs that critically control the synchronized spontaneous firing and pulsatile release of gonadotropin-releasing hormone in GT1-7 neurons.
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