Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retrograde signaling by endocannabinoids (eCBs) mediates a widely expressed form of long-term depression at excitatory and inhibitory synapses (eCB-LTD), involving a reduction in neurotransmitter release. In the hippocampus, eCB-LTD occurs at interneuron (IN)-pyramidal cell (PC) synapses (I-LTD), and its induction requires a presynaptic reduction of cAMP/PKA signaling resulting from minutes of type 1 cannabinoid receptor (CB1R) activation. Although repetitive activity of glutamatergic synapses initiates the eCB mobilization required for I-LTD, it is unclear whether CB1R-containing GABAergic terminals are passive targets of eCBs or whether they actively contribute to induction. Here, we show that the minutes-long induction period for I-LTD may serve as a window to integrate associated spontaneous activity in the same IN receiving the retrograde eCB signal. Indeed, reducing spontaneous IN firing blocked I-LTD, which could be rescued with extra stimulation of inhibitory afferents. Moreover, cell pair recordings showed that a single IN expressed LTD onto a PC only if it was active during eCB signaling. Several methods of disrupting presynaptic Ca(2+) dynamics all blocked I-LTD, strongly suggesting that IN spikes regulate I-LTD by raising Ca(2+) at the nerve terminal. Finally, inhibiting the Ca(2+)-activated phosphatase, calcineurin, fully blocked I-LTD, but blocking another phosphatase did not. Our findings support a model where both CB1R signaling and IN activity shift the balance of kinase and phosphatase activity in the presynaptic terminal to induce I-LTD.
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PMID:Interneuron activity controls endocannabinoid-mediated presynaptic plasticity through calcineurin. 1863 63

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, affecting 10-20% of children and 2% of adults worldwide. Preventive treatment of AD consists of daily skin hydration and emollient therapy; but the majority of patients still require symptomatic treatment with topical corticosteroids and/or topical calcineurin inhibitors, both of which may be associated with potential long-term side effects. With increasing evidence supporting the role of skin barrier defects in the pathogenesis of AD, there is also a parallel increase in medications that claim to assist barrier repair. The current review discusses some exciting results with these medications, as well as the challenges that lie ahead of them. While barrier repair treatments offer some promise, there continues to be a need for safer anti-inflammatory medications. Some of these medications under investigation are phosphodiesterase-4 inhibitors, urocanic acid oxidation products and IL-4/IL-13 receptor blockers. The review also discusses anti-staphylococcal treatments including nanocrystalline silver cream, silver and antimicrobial-coated fabrics, and anti-itch treatments including mu-opiod receptor antagonists, chymase inhibitors and cannabinoid receptor agonists. These medications may become an integral part of AD therapy.
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PMID:Emerging drugs for atopic dermatitis. 1921 4

The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression was a result of Ca(2+)-calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor-independent manner. Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses.
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PMID:TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. 2121 72