Cross-Modulation and Molecular Interaction at the Ca_v3.3 Protein between the Endogenous Lipids and the T-Type Calcium Channel Antagonist TTA-A2.

N-Acyldopamines and N-Acylserotonins: From Synthetic Pharmacological Tools to Endogenous Multitarget Mediators

“…Apart from the aforementioned inhibition of FAAH and competitive antagonism of TRPV1, NASs, like NADs, have been also suggested to act as: (1) agonists for GPR119 (in the case of N-oleoyl-serotonin [74]), which agrees with the preliminary finding of their stimulatory action on GLP-1 secretion [8]; and (2) inhibitors of T-type Ca 2+ channels [75], which may underlie some of their analgesic action. Furthermore, AA-5-HT inhibited the release of b-hexosaminidase (IC 50 = 13.58 mM), a marker of degranulation, and TNF-a (IC 50 = 12.52 mM), a proinflammatory cytokine, in IgE-activated RBL-2H3 cells [76].…”

“…Among the non-TRPV1 and non-CB1 mediated actions of NADs so far reported, the capability of inhibiting T-type calcium channels is the one that can be exerted at the lowest (submicromolar) concentrations, and was confirmed in at least two independent studies, especially for the unsaturated members of this family such as NADA [37,38]. It would be interesting to assess if this effect of NADs, together with TRPV1 activation/desensitization, underlies, to some extent, their antihyperalgesic actions (see above); or if it is at the basis of the observation that NADA, like anandamide, inhibits K + -evoked Ca 2+ entry and transmitter release in hippocampal neurons, an effect shown to occur independently of CB1 and TRPV1 receptors and possibly through direct Ca 2+ channel blockade [39].…”

Endocannabinoids and Their Pharmacological Actions

“…Thus, evidence has been obtained that this compound can inhibit T-type Ca 2þ currents with quite high efficacy both in Ca v 3.1, Ca v 3.2 and Ca v 3.3 channels expressed in HEK-293 cells, with IC 50 values of 513 nM, 1.1 μM and 355 nM, respectively, and in mouse isolated trigeminal ganglion neurons at 300 nM (Ross et al 2009). In a more recent investigation, however, it was found that 3 μM N-arachidonoyldopamine displayed rather low efficacy as an inhibitor of Ca v 3.1, Ca v 3.2 and Ca v 3.3 currents, compared, for example, with anandamide, and also that it could antagonize inhibition of Ca v 3.3 currents induced by the selective T-channel inhibitor, TTA-A2 (Cazade et al 2014). It was also found in the latter investigation that N-arachidonoyldopamine can displace […”

The Endocannabinoid System and its Modulation by Phytocannabinoids

“…Another orphan GPCR, GPR18, is instead activated by N-arachidonoyl-glycine and by a synthetic CBD analogue known as abnormal-cannabidiol [47,48]. 2) Ttype Ca 2+ channels have been suggested to be inhibited by both unsaturated long chain fatty acid amides, including some N--acylethanolamines, N-acyl-serotonins, and N-acyldopamines [49], and THC and CBD [50]. 3) peroxisome-proliferator activated receptor-α is activated by both anandamide congeners such as N-palmitoylethanolamine and N-oleoylethanolamine [51], which have in this nuclear receptor their preferred target, and some plant and synthetic cannabinoids [52]; instead, PPARγ is activated, at concentrations of 1-10 μM, by both CBD and anandamide or 2-AG [53,54].…”