Metabotropic glutamate receptor 5 regulates excitability and Kv4.2-containing K⁺ channels primarily in excitatory neurons of the spinal dorsal horn

Abstract

ϩ channel subunit underlies A-type currents in spinal cord dorsal horn neurons and that this channel is modulated by mGlu5-ERK signaling. In the present study, we tested the hypothesis that modulation of Kv4.2 by mGlu5 occurs in excitatory spinal dorsal horn neurons. With the use of a transgenic mouse strain expressing enhanced green fluorescent protein (GFP) under control of the promoter for the ␥-amino butyric acid (GABA)-synthesizing enzyme, glutamic acid decarboxylase 67 (GAD67), we found that these GABAergic neurons express less Kv4.2-mediated A-type current than non-GAD67-GFP neurons. Furthermore, the mGlu1/5 agonist, (R,S)-3,5-dihydroxyphenylglycine, had no modulatory effects on A-type currents or neuronal excitability in this subgroup of GABAergic neurons but robustly modulated A-type currents and neuronal excitability in non-GFP-expressing neurons. Immunofluorescence studies revealed that Kv4.2 was highly colocalized with markers of excitatory neurons, such as vesicular glutamate transporter 1/2, PKC␥, and neurokinin 1, in cultured dorsal horn neurons. These results indicate that mGlu5-Kv4.2 signaling is associated with excitatory dorsal horn neurons and suggest that the pronociceptive effects of mGlu5 activation in the spinal cord likely involve enhanced excitability of excitatory neurons.

Multiple T-type Ca2+ current subtypes in electrophysiologically characterized hamster dorsal horn neurons: possible role in spinal sensory integration

“…Moreover, calcium entry from T-channels can also regulate the function of low-voltage-activated A-type K ϩ channels (Anderson et al 2010). A-type K ϩ channels are also widely expressed in dorsal horn neurons (Grudt and Perl 2002;Hu and Gereau 2011;Huang et al 2005;Walsh et al 2009), suggesting that I T may control firing frequency and timing by this mechanism as well. The influence of T-type channels on neuronal firing via modulation of K ϩ channel function would appear to be strongest for SB-type phasic cells, which express the largest I T .…”

Presynaptic Release-Regulating mGlu1 Receptors in Central Nervous System

“…The mGlu5 receptor subtype was proposed to play the major role in these events (Hu et al, 2007; Hu and Gereau, 2011), but the participation of mGlu1 receptor subtypes was not excluded (Mills et al, 2001). …”

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

“…[67][68][69][70][71] Various transgenic mouse line in which inhibitory neurons are labeled with GFP have also been used to characterize inhibitory neurons in the spinal dorsal horn. 5,7,[71][72][73][74][75][76][77][78] Identification and systematic classification of the full set of different inhibitory and excitatory cell types awaits careful genetic dissection. 14,79 Some notable observations emerge from Fig.…”