Endocannabinoids mediate muscarine-induced synaptic depression at the vertebrate neuromuscular junction
نویسندگان
چکیده
Endocannabinoids (eCBs) inhibit neurotransmitter release throughout the central nervous system. Using the Ceratomandibularis muscle from the lizard Anolis carolinensis we asked whether eCBs play a similar role at the vertebrate neuromuscular junction. We report here that the CB(1) cannabinoid receptor is concentrated on motor terminals and that eCBs mediate the inhibition of neurotransmitter release induced by the activation of M(3) muscarinic acetylcholine (ACh) receptors. N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, a CB(1) antagonist, prevents muscarine from inhibiting release and arachidonylcyclopropylamide (ACPA), a CB(1) receptor agonist, mimics M(3) activation and occludes the effect of muscarine. As for its mechanism of action, ACPA reduces the action-potential-evoked calcium transient in the nerve terminal and this decrease is more than sufficient to account for the observed inhibition of neurotransmitter release. Similar to muscarine, the inhibition of synaptic transmission by ACPA requires nitric oxide, acting via the synthesis of cGMP and the activation of cGMP-dependent protein kinase. 2-Arachidonoylglycerol (2-AG) is responsible for the majority of the effects of eCB as inhibitors of phospholipase C and diacylglycerol lipase, two enzymes responsible for synthesis of 2-AG, significantly limit muscarine-induced inhibition of neurotransmitter release. Lastly, the injection of (5Z,8Z,11Z,14Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide (an inhibitor of eCB transport) into the muscle prevents muscarine, but not ACPA, from inhibiting ACh release. These results collectively lead to a model of the vertebrate neuromuscular junction whereby 2-AG mediates the muscarine-induced inhibition of ACh release. To demonstrate the physiological relevance of this model we show that the CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide prevents synaptic inhibition induced by 20 min of 1-Hz stimulation.
منابع مشابه
Molecular mechanisms underlying maturation and maintenance of the vertebrate neuromuscular junction.
The vertebrate neuromuscular junction (NMJ), a peripheral synapse formed between motoneuron and skeletal muscle, is characterized by a protracted postnatal period of maturation and life-long maintenance. In neuromuscular disorders such as congenital myasthenic syndromes (CMSs), disruptions of NMJ maturation and/or maintenance are frequently observed. In particular, defective neuromuscular trans...
متن کاملModulation of Synaptic Efficacy and Synaptic Depression by Glial Cells at the Frog Neuromuscular Junction
The ability of perisynaptic glial cells to modulate transmitter release and synaptic depression was studied at the frog neuromuscular junction (nmj). Injection of GTPgammaS in perisynaptic Schwann cells (PSCs), glial cells at this synapse, induced a reduction in the amplitude of nerve-evoked synaptic responses but had no effect on the frequency, the amplitude, or the duration of the miniature e...
متن کاملRequirement of Akt to mediate long-term synaptic depression in Drosophila.
Drosophila larval neuromuscular junction (NMJ) is a well established preparation enabling quantitative analyses of synaptic physiology at identifiable synapses. Here, we report the first characterization of synaptic long-term depression (LTD) at the Drosophila NMJ. LTD can be reliably induced by specific patterns of tetanic stimulation, and the level of LTD depends on both stimulus frequency an...
متن کاملEndocannabinoids Mediate Synaptic Plasticity at Mixed Synapses
Endocannabinoids are generally known to suppress excitatory or inhibitory synaptic transmission. Now, in an elegant series of experiments, Cachope et al. reveal a novel signaling pathway whereby endocannabinoids indirectly potentiate mixed chemical and electrical synapses. Gap junction-mediated transmission can thus be potentiated via distinct frequency-dependent mechanisms.
متن کاملModulation of Synaptic Vesicle Exocytosis in Muscle-Dependent Long-Term Depression at the Amphibian Neuromuscular Junction
We have labeled recycling synaptic vesicles at the somatic Bufo marinus neuromuscular junction with the styryl dye FM2-10 and provide direct evidence for refractoriness of exocytosis associated with a muscle activity-dependent form of long-term depression (LTD) at this synapse. FM2-10 dye unloading experiments demonstrated that the rate of vesicle exocytosis from the release ready pool (RRP) of...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- The European Journal of Neuroscience
دوره 25 شماره
صفحات -
تاریخ انتشار 2007