MrgD Activation Inhibits KCNQ/M-Currents and Contributes to Enhanced Neuronal Excitability

Crozier, Robert A.; Ajit, Seena K.; Kaftan, Edward; Pausch, Mark H.

doi:10.1523/jneurosci.4932-06.2007

Cited by 96 publications

(86 citation statements)

References 31 publications

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“…The KCNQ/M-currents in small DRG neurons are large with less contamination of other currents, and therefore are more reliable and suitable for pharmacological manipulations 17,37 . Because DRG neurons are highly refractory to fire repetitively, another characteristic of KCNQ-expressing neurons, we utilized a higher concentration of ghrelin (300 nM) in this study.…”

Section: Inhibition Of Voltage-dependent Kcnq/m-currents By Ghrelinmentioning

confidence: 99%

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

Shi

Bian

et al. 2013

Nat Commun

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The gut-derived orexigenic peptide hormone ghrelin enhances neuronal firing in the substantia nigra pars compacta, where dopaminergic neurons modulate the function of the nigrostriatal system for motor coordination. Here we describe a novel mechanism by which ghrelin enhances firing of nigral dopaminergic neurons by inhibiting voltage-gated potassium Kv7/KCNQ/M-channels through its receptor GHS-R1a and activation of the PLC-PKC pathway. Brain slice recordings of substantia nigra pars compacta neurons reveal that ghrelin inhibits native Kv7/KCNQ/M-currents. This effect is abolished by selective inhibitors of GHSR1a, PLC and PKC. Transgenic suppression of native Kv7/KCNQ/M-channels in mice or channel blockade with XE991 abolishes ghrelin-induced hyperexcitability. In vivo, intracerebroventricular ghrelin administration causes increased dopamine release and turnover in the striatum. Microinjection of ghrelin or XE991 into substantia nigra pars compacta results in contralateral dystonic posturing, and attenuation of catalepsy elicited by systemic administration of the D2 receptor antagonist haloperidol. Our findings indicate that the ghrelin/ KCNQ signalling is likely a common pathway utilized by the nervous system.

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Section: Inhibition Of Voltage-dependent Kcnq/m-currents By Ghrelinmentioning

confidence: 99%

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

Shi

Bian

et al. 2013

Nat Commun

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“…Nevertheless, these M 1 receptors exert a robust excitatory effect in sympathetic neurons by inhibiting M current via PIP 2 depletion (18,19). DRG neurons also express M channels [Kv7.2, Kv7.3, and Kv7.5 (20,21)], and M-channel inhibition produces strong excitatory effects in DRG (12,20,22,23). Therefore, we tested whether SP inhibits M current in DRG and TG neurons.…”

Section: Sp Augments M Current In Sensory Neurons Via Oxidativementioning

confidence: 99%

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Linley¹,

Ooi

Pettinger³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

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Substance P (SP) is a prominent neuromodulator, which is produced and released by peripheral damage-sensing (nociceptive) neurons; these neurons also express SP receptors. However, the mechanisms of peripheral SP signaling are poorly understood. We report a signaling pathway of SP in nociceptive neurons: Acting predominantly through NK1 receptors and G i/o proteins, SP stimulates increased release of reactive oxygen species from the mitochondrial electron transport chain. Reactive oxygen species, functioning as second messengers, induce oxidative modification and augment M-type potassium channels, thereby suppressing excitability. This signaling cascade requires activation of phospholipase C but is largely uncoupled from the inositol 1,4,5-trisphosphate sensitive Ca 2+ stores. In rats SP causes sensitization of TRPV1 and produces thermal hyperalgesia. However, the lack of coupling between SP signaling and inositol 1,4,5-trisphosphate sensitive Ca 2+ stores, together with the augmenting effect on M channels, renders the SP pathway ineffective to excite nociceptors acutely and produce spontaneous pain. Our study describes a mechanism for neurokinin signaling in sensory neurons and provides evidence that spontaneous pain and hyperalgesia can have distinct underlying mechanisms within a single nociceptive neuron.G protein coupled receptors | inflammatory pain | intracellular signaling | KCNQ | M current E xcitation of peripheral terminals of sensory neurons is a primary event in somatosensation, including pain. A large proportion of sensory neurons (mostly TRPV1 + damage-sensing or "nociceptive" neurons) produce neuropeptides such as substance P (SP), which are released in response to nociceptive stimulation both at spinal cord synapses and in the periphery (1). In the spinal cord SP acts as an excitatory neurotransmitter or cotransmitter (2, 3), whereas peripheral SP release is thought to underlie the inflammatory response known as "neurogenic inflammation" (4). Many peripheral nociceptors also express receptors for SP [neurokinin receptors (NKR) 1-3 (NK1-3)]; this expression may suggest paracrine or autocrine actions of this peptide. However, the nature of such actions is controversial, and the molecular events triggered by NKR in peripheral nociceptors are not well established. The NKR traditionally are classed as G q/11 -coupled G protein-coupled receptors (GPCR) that activate phospholipase C (PLC), with subsequent hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate (PIP 2 ) and release of inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG) (5, 6). Common downstream steps of G q/11 signaling include IP 3 -mediated release of Ca 2+ from intracellular stores and DAG-mediated activation of PKC. However, it was hitherto unknown whether NKR in peripheral sensory neurons couple fully to this signaling cascade, because a lack of coupling between NKR and Ca 2+ release in dorsal root ganglia (DRG) neurons has been noted (ref. 7 and 8, but cf. ref. 9). Nevertheless, it is accepted that peripherally act...

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“…When ingested in pure form, peak concentrations of beta-alanine appear in the blood within the first hour and rapidly decline within the second hour [3]. Doses of more than 10 mg/kg body weight are to be avoided, since circulating beta-alanine concentrations above 100 µM give rise to parasthesia symptoms, that probably relate to a sensitization of nociceptive neurons in the skin involved in neuropathic pain [85]. A daily dose of 4.8 to 6.4g therefore requires 6-8 servings, separated by at least 2h.…”

Section: Beta-alanine Supplementationmentioning

confidence: 99%

Muscle Carnosine Metabolism and β-Alanine Supplementation in Relation to Exercise and Training

et al. 2010

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MrgD Activation Inhibits KCNQ/M-Currents and Contributes to Enhanced Neuronal Excitability

Cited by 96 publications

References 31 publications

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

Reactive oxygen species are second messengers of neurokinin signaling in peripheral sensory neurons

Muscle Carnosine Metabolism and β-Alanine Supplementation in Relation to Exercise and Training

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