Roles of K+ and cation channels in ORL-1 receptor-mediated depression of neuronal excitability and epileptic activities in the medial entorhinal cortex

Abstract

Nociceptin (NOP) is an endogenous opioid-like peptide that selectively activates the opioid receptor-like (ORL-1) receptors. The entorhinal cortex (EC) is closely related to temporal lobe epilepsy and expresses high densities of ORL-1 receptors. However, the functions of NOP in the EC, especially in modulating the epileptiform activity in the EC, have not been determined. We demonstrated that activation of ORL-1 receptors remarkably inhibited the epileptiform activity in entorhinal slices induced by application of picrotoxin or by deprivation of extracellular Mg 2+. NOP-mediated depression of epileptiform activity was independent of synaptic transmission in the EC, but mediated by inhibition of neuronal excitability in the EC. NOP hyperpolarized entorhinal neurons via activation of K + channels and inhibition of cation channels. Whereas application of Ba 2+ at 300 μM which is effective for the inward rectifier K + (Kir) channels slightly inhibited NOP-induced hyperpolarization, the current-voltage (I-V) curve of the net currents induced by NOP was linear without showing inward rectification. However, a role of NOPinduced inhibition of cation channels was revealed after inhibition of Kir channels by Ba 2+. Furthermore, NOP-mediated augmentation of membrane currents was differently affected by application of the blockers selective for distinct subfamilies of Kir channels. Whereas SCH23390 or ML133 blocked NOP-induced augmentation of membrane currents at negative potentials, application of tertiapin-Q exerted no actions on NOP-induced alteration of membrane currents. Our results demonstrated a novel cellular and molecular mechanism whereby activation of ORL-1 receptors depresses epilepsy.

Oxytocin receptors excite lateral nucleus of central amygdala by phospholipase Cβ‐ and protein kinase C‐dependent depression of inwardly rectifying K+channels

“…2017; Li et al . 2019), we included 300 µ m Ba 2+ in the extracellular solution to inhibit Kir channels. Bath application of 300 µ m Ba 2+ indeed inhibited a current showing inward rectification ( n = 14, Fig.…”

“…To prevent potential desensitization induced by repeated applications of the agonist, one slice was limited to only one application of TGOT. Frequency of APs was calculated by Mini Analysis 6.0.1 (Synaptosoft Inc., Decatur, GA, USA), as described previously (Li et al 2019). Resting membrane potentials (RMPs) and holding currents (HCs) at −60 mV were recorded in the extracellular solution supplemented with tetrodotoxin (TTX, 0.5 µM), kynurenic acid (1 mM) and picrotoxin (100 µM).…”

“…Because micromolar concentration of Ba 2+ (100-300 µM) has been shown to block Kir channels by at least 80% (Lacey et al 1988;Hu et al 2017;Li et al 2019), we included 300 µM Ba 2+ in the extracellular solution to inhibit Kir channels. Bath application of 300 µM Ba 2+ indeed inhibited a current showing inward rectification (n = 14, Fig.…”

Neuromodulation of Astrocytic K+ Clearance

“…Extracellular K + dynamics are determined by the rate of active K + uptake into nearby astrocytes, as well as the rate of extracellular diffusion [ 67 ]. If not cleared, increased extracellular K + can lead to altered network oscillations and ictal activity [ 66 , 68 ]. Previous reports suggested that the rate of K + clearance can also be affected by different factors, including temperature [ 32 ], ammonia [ 69 ], glutamate [ 40 ], and pH, however, the cellular mechanisms affecting this clearance process are still largely unknown.…”

Roles of PLCβ, PIP2, and GIRK channels in arginine vasopressin‐elicited excitation of CA1 pyramidal neurons

“…We used a voltage clamp and recorded the holding currents at −60 mV in response to bath application of AVP. Bath application of AVP induced an inward holding current in K + -gluconate-containing intracellular solution (−15.9 ± 3.2 pA, n = 14, p = .0002 vs. baseline, Wilcoxon test; Figure 7 Micromolar concentration of Ba 2+ (100-300 μM) has been shown to block Kir channels by at least 80% (Hu et al, 2017;Lacey et al, 1988;Li et al, 2019). We thus included 300 μM Ba 2+ in the extracellular solution to inhibit Kir channels and tested the effects of Ba 2+ on AVP-induced inward currents.…”