The conantokins are a diverse array of seventeen-27-amino acid residue peptides identified in the venoms of maritime snails of the genus Conus that support the hostTelepathine in the capture of prey and enable their protection from predators [1]. The very first conantokin discovered, conantokin-G (ConG), was purified and characterized from Conus geographus [two]. Later on a selection of conantokins, this kind of as ConT [3] and ConR [four], were found and characterized from other looking snail species. Notably, these peptides have numerous conserved gammacarboxyglutamate (Gla) residues that are central to their biological action, viz., selective inhibition of ion movement via the Glu/Gly co-agonized channels of the N-methyl-D-aspartate receptor (NMDAR) [2]. Moreover, the Gla residues give rise to a rigid conformation of the peptides, specially in the existence of divalent cations, which stabilizes an -helical conformation of the conantokins, and permits for peptide dimerization [5]. Nonetheless, the extent of -helical conformation differs in between these peptides. ConT assumes a large diploma of -helicity in the steel-totally free (apo) state, whereas ConG adopts a random conformation in absence of divalent ions [six,seven]. However, ConG binds to divalent cations to create an -helical structure equivalent to apo- or metal-certain ConT [eight]. Given that the initial conantokin was noted above two a long time ago, these peptides have created desire as selective antagonists of the NMDAR. The Glu/Gly co-activated NMDAR is a voltage- and ligand-gated ion channel, which plays an important role in excitatory synaptic transmission, with ramifications in plasticity, understanding, and memory. The useful NMDAR of the Central Anxious System (CNS) is a heterotetramer composed of two classes of subunits. The Glybinding GluN1 subunit is ubiquitously expressed and belongs to a single of its eight splice variants, GluN1a-GluN1h. This coassembles with a Glu binding GluN2 subunit, the expression of which may differ spatially and temporally [9]. The GluN2 household is composed of four various subunits, GluN2A-GluN2D, encoded by separate genes [ten]. The actual subunit composition of the NMDAR establishes distinctions in binding of agonists and antagonists [eleven]. Though NMDARs are important for mediating advancement and normal synaptic transmission, they are excessively activated in several neuropathologies [12,thirteen]. For illustration, stories have shown the involvement of the GluN2B subunit of an NMDAR subset in Huntington’s disease [fourteen], epileptogenesis [15], and opiate dependancy [sixteen], amid others. For that reason, GluN2B-certain antagonistic exercise is a much-sought residence as neuroprotective medications, as opposed to significantly less appealing substantial affinity NMDAR ion channel blockers [17]. Toward this conclude, the GluN2B-specificity of ConG has been exploited as an anti-convulsive and an analgesic agent [18,19], as effectively as a neuroprotective agent for publish-ischemic injuries [20,21]. Just lately, other conantokins ended up identified in the venom of the Indo-PHematoporphyrinacific fish hunting cone snail, C. parius. These peptides, discovered as ConPr1, ConPr2, and ConPr3, differ in many residues from other Gla-containing conantokins formerly noted, this sort of as the absence of Gla at placement three, and the presence of 3 distinct submit-translational modifications in ConPr3, viz., Gla residues, a hydroxyproline residue at placement 3, and C-terminal amidation [22]. Regardless of these variances, these peptides exhibited high inhibitory efficiency for GluN2B-that contains NMDARs, which had been transfected into Xenopus oocytes [22]. Even so, the specificities and efficacies of these peptides, and their effects on signaling downstream of the NMDAR, were not tested in physiologically-relevant neuronal cells that incorporate a sophisticated technique of dynamic receptors. In the previous, we have documented that the inhibition by ConG, ConT, and ConR of NMDA/Glystimulated intracellular Ca2+ (iCa2+) inflow influenced downstream activation of the transcription issue, cAMP response elementbinding protein (CREB) at Ser133, a property that depended on neuron maturity [23]. In the recent research, the ex vivo organic action of this new family members of peptides has been evaluated by doing total cell patch clamp recent recordings in experienced main neurons derived from wild-kind (WT), GluN2A-/-, and GluN2B-/- mouse cortices, and people from the rat hippocampus. Selectivity towards NMDAR subunits was calculated by means of real-time adjustments in iCa2+. Given that Ca2+ influx is immediately linked to downstream signaling pursuits, this review also afforded an comprehending of the consequences of these particular peptides on CREB signaling.