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Neuropeptide Receptor-Ion Channel Coupling in the Mammalian Brain
Published in Gerard O’Cuinn, Metabolism of Brain Peptides, 2020
The action of substance P (and neurokinins selective for NK1 receptors) in the rat brain is excitatory, with low (sub-micromolar) concentrations of the peptide producing a long lasting slow neuronal depolarization, such as that seen when substance P is applied to neurones in the gustatory zone of the nucleus tractus solitarius30. This effect is similar to that seen on application of CCK to VMH neurones. Indeed, some authors have suggested that substance P acts to close a muscarine-sensitive time- and voltage-dependent outward current (M-current or IK(M)) on sympathetic neurones (reviewed in3). Others have concluded that the predominant substance P-sensitive current is another potassium current, the inward rectifier or IK(IR) which differs kinetically from the M-current. Stanfield et al.31 showed that substance P reduced the inward rectification of cultured neurones of the rat nucleus basalis and Yamaguchi et al.32 used whole-cell recording from the same type of cells to show that IK(IR) was blocked by substance P in these cholinergic neurones of the forebrain, an effect which was not altered by the presence of sodium nitroprusside, suggesting that the production of cyclic GMP was not a prerequisite for substance P action.
Transmitter/Peptide Interactions in NTS Neuronal Circuits
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
Several noninactivating potassium currents including anomalous rectification, the Q-current, and leak currents together with the M-current are involved in depolarizing responses associated with an increase of the input resistance. The M-current is a time- and voltage-dependent potassium current that persists at slightly depolarized membrane potentials and is thought to clamp neuronal membrane at potentials near rest. IM is reduced by muscarinic cholinergic agonists, serotonin, the amino acid agonist, quisqualate, and certain peptides (e.g., LHRH, subP, and bradykinin).36 In voltage-clamped neurons of the NTS,7 the M-current is best seen with holding potentials of —40 mV and hyperpolarizing command steps of 5 to 25 mV. It appears as a slow, inward current relaxation following the instantaneous (ohmic) inward current drop. As the instantaneous current jump at command onset is larger than at command offset, the relaxation represents the slow inactivation of an outward potassium current. Muscarine abolishes the relaxation and generates an inward current causing a membrane depolarization, an increase of the input resistance and therefore neuronal excitation.
Drugs Affecting Autonomic Ganglia (Including the Adrenal Medulla)
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
The muscarinic inhibition of the M-current involved in the slow EPSP is mediated by G-protein activation. This is not susceptible to ADP-ribosylation by pertussis toxin, suggesting that Gi or G° are not involved. Recent evidence suggests that Gq and/or G11 may be responsible (Caulfield et al. 1994). Changes in cAMP or cGMP are probably not involved but increased production of inositol phosphates, including IP3, has been observed. Thus, G protein-coupled stimulation of phospholipase C activity is likely to be the mediator of M-current supression by muscarinic agonists (Buckley & Caulfield 1992) (see Chapter 13).
Personalized treatment in the epilepsies: challenges and opportunities
Published in Expert Review of Precision Medicine and Drug Development, 2018
Simona Balestrini, Sanjay M Sisodiya
The KCNQ2 and KCNQ3 genes encode subunits of the voltage-gated potassium M channel underlying the neuronal M-current [60] and are amongst the most common causes of neonatal epileptic encephalopathy of widely varying severity [61]. In KCNQ2/KCNQ3-related epilepsy, there is a potential tailored precision medicine strategy with the use of retigabine (ezogabine), a drug primarily acting as a positive allosteric modulator of KCNQ2-5 (Kv7.2–7.5) ion channels, and the first neuronal potassium (K+) channel opener licensed for the treatment of epilepsy [62]. In vitro studies identified the probable binding site of retigabine in KCNQ2 and KCNQ3 channels, explaining its voltage-dependent activating effect through a hyperpolarizing shift of the activation curve [63]. Retigabine has been shown to partially reverse the effect of KCNQ2 mutations in cell models [64].
Emerging drugs for focal epilepsy
Published in Expert Opinion on Emerging Drugs, 2018
Potassium channels are ubiquitous in neuronal and glial cell membranes and they are central to excitability [35]. Among all voltage-gated potassium currents, the M-current has been historically linked to epilepsy with the discovery of benign familial neonatal seizures, a rare autosomal dominant condition associated with mutations of KCNQ subfamily genes [36]. Retigabine is the prototype of potassium channels openers and represents the first in-class AED marketed so far. It is a structure analog of Flupirtine, a centrally acting nonopioid analgesic with also muscle relaxant and neuroprotective properties [37,38]. It was already known since the 1980s that Flupirtine had some anticonvulsant activity and its subsequent structure-activity optimization let to the development of Retigabine [39]. In 2013, shortly after having been marketed, GlaxoSmithKline (GSK) announced that there were safety issues with the drug as it could cause blue discoloration of the skin and eye abnormalities. As a consequence, GSK decided to discontinue the production of Retigabine in 2017. However, research on the potential role of potassium channel openers is epilepsy has progressed with the identification of other potential drugs like 1OP-2198.
The role of Gα protein signaling in the membrane estrogen receptor-mediated signaling
Published in Gynecological Endocrinology, 2021
Shuhui Zheng, Lin Wu, Chao Fan, Jingxia Lin, Yaxing Zhang, Tommaso Simoncini, Xiaodong Fu
The hypothalamus–pituitary–adrenal (HPA) axis is the key factor of depressive disorders[66]. In the hypothalamic paraventricular nucleus (PVN), CRH neurons play a central role in HPA axis regulation. Recently, E2 was found to regulate the M-current in PVN CRH neurons. Hu et al. [59] found that activation of Gq-mER by E2 rapidly suppresses the M-current and potentiated glutamatergic excitatory postsynaptic currents in PVN CRH neurons through the Gq-coupled PLC-PKC-PKA pathway (Figure 3).