GIRK2 splice variants and neuronal G protein-gated K+ channels: implications for channel function and behavior

Abstract

Many neurotransmitters directly inhibit neurons by activating G protein-gated inwardly rectifying K+ (GIRK) channels, thereby moderating the influence of excitatory input on neuronal excitability. While most neuronal GIRK channels are formed by GIRK1 and GIRK2 subunits, distinct GIRK2 isoforms generated by alternative splicing have been identified. Here, we compared the trafficking and function of two isoforms (GIRK2a and GIRK2c) expressed individually in hippocampal pyramidal neurons lacking GIRK2. GIRK2a and GIRK2c supported comparable somato-dendritic GIRK currents in Girk2 −/− pyramidal neurons, although GIRK2c achieved a more uniform subcellular distribution in pyramidal neurons and supported inhibitory postsynaptic currents in distal dendrites better than GIRK2a. While over-expression of either isoform in dorsal CA1 pyramidal neurons restored contextual fear learning in a conditional Girk2 −/− mouse line, GIRK2a also enhanced cue fear learning. Collectively, these data indicate that GIRK2 isoform balance within a neuron can impact the processing of afferent inhibitory input and associated behavior.

Acetylcholine release inhibits distinct excitatory inputs onto hippocampal CA1 pyramidal neurons via different cellular and network mechanisms

“…In contrast, GABAB receptors are segregated from this complex in dendritic shafts, which suggests that in CA1 PC dendrites GABAB activation of GIRK channels maybe primarily confined to the dendritic spines. Considering that GIRK2 channels appear to be necessary for GABAB IPSP activation in CA1 PCs (Marron Fernandez de Velasco et al 2017), it is possible that the GABAB-mediated postsynaptic inhibition of SR inputs measured in our studies was confined to the synaptic spine and conductance changes could not be measured at the soma. Thus, suppression of SR inputs in individual spines of CA1 PCs may provide a mechanism for selective inhibition of individual synapses on CA1 PCs.…”

Direct activation of G-protein-gated inward rectifying K+ channels promotes nonrapid eye movement sleep

“…They can also be modulated by neuropeptides such as nociceptin/orphanin FQ (N/OFQ) through NOP receptors [36]. The hippocampal pyramidal neurons are well-defined to express abundant GIRK1/2 channels [52,53] and its functional modulation by a variety of metabotropic receptors (GABA B , metabotropic glutamate receptors, muscarinic, adenosine A1, opioid µ receptors, etc.) has been documented [54,55].…”

VU0810464, a non‐urea G protein‐gated inwardly rectifying K+ (Kir3/GIRK) channel activator, exhibits enhanced selectivity for neuronal Kir3 channels and reduces stress‐induced hyperthermia in mice

“…Specifically, VU0810464‐induced currents were compared with currents evoked by either the GABA B receptor agonist baclofen (HPC neurons) or the muscarinic (M 2 ) receptor agonist carbachol (SAN cells), standard agonists that evoke robust and reliable K ir 3 currents in neurons and cardiac myocytes, respectively (Wydeven, Posokhova, et al, ; Wydeven et al, ). In HPC neurons, currents evoked by 10‐μM VU0810464 were similar to those evoked by a saturating concentration of baclofen (Figure b,c; Marron Fernandez de Velasco et al, ). In contrast, currents evoked by a saturating concentration of VU0810464 (30 μM) in SAN cells were significantly smaller than maximal carbachol‐induced currents (Figure d,e; Wydeven, Posokhova, et al, ).…”

“…Primary cultures of hippocampal (HPC) neurons were prepared as described previously (Marron Fernandez de Velasco et al, ). Briefly, extracted hippocampi from neonatal (P0–3) pups were placed into an ice‐cold modified HBSS (Thermo Fisher), 10‐mM HEPES‐NaOH pH 7.3 (Thermo Fisher), 0.02% ( w / v ) Pluronic F‐127, and 1.5‐μM Thallos‐AM (TEFlabs, Austin, TX).…”

“…Primary cultures of hippocampal (HPC) neurons were prepared as described previously (Marron Fernandez de Velasco et al, 2017).…”