Disease relevance of Kcnj3

• Molecular determinants for activation of G-protein-coupled inward rectifier K+ (GIRK) channels by extracellular acidosis [1].
• 1. The contribution of endogenous regulators of G protein signalling (RGS) proteins to G protein modulated inwardly rectifying K(+) channel (GIRK) activation/deactivation was examined by expressing mutants of Galpha(oA) insensitive to both pertussis toxin (PTX) and RGS proteins in rat sympathetic neurons [2].
• It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro [3].

Psychiatry related information on Kcnj3

• Unlike for acute electroconvulsive shock, GIRK1 messenger RNA abundance in the dentate gyrus was significantly increased after chronic electroconvulsive shock [4].

High impact information on Kcnj3

• Here we report that the same signaling pathway in the postsynaptic CA1 pyramidal neuron also causes LTP of the slow inhibitory postsynaptic current (sIPSC) mediated by metabotropic GABA(B) receptors (GABA(B)-Rs) and G protein-activated inwardly rectifying K(+) (GIRK) channels, both residing in dendritic spines as well as shafts [5].
• It is now shown that IKACh is a heteromultimer of two distinct inwardly rectifying K(+)-channel subunits, GIRK1 and a newly cloned member of the family, CIR [6].
• Based on sequence homology with cloned inwardly rectifying K+ channels, ROMK1 (ref. 11) and IRK1 (ref. 12), we have isolated a complementary DNA for a G-protein-coupled inwardly rectifying K+ channel (GIRK1) from rat heart [7].
• In hippocampal neurons, expression of LGN, or LGN fragments that mimic or enhance LGN activity, hyperpolarizes the resting potential due to increased basal GIRK activity and reduces excitability [8].
• Such rich trafficking behaviors provide a mechanism for dynamic regulation of GIRK channel density in the plasma membrane [9].

Chemical compound and disease context of Kcnj3

• 3. NA-mediated activation of GIRK channels was abolished by pertussis toxin (PTX) pretreatment, indicating coupling via G proteins of the Gi/Go subfamily [10].
• The peptides were administered alone or combined with an inhibitor of Gi protein pertussis toxin (PTX), Gi-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), G(q/11) protein inhibitor [D-Arg1,D-Trp(5,7,9),Leu11]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene [11].
• SST, acting via sst(5) receptors and pertussis toxin-sensitive G-proteins, activated an inwardly rectifying K(+) (GIRK) current in 20 of 28 recorded cells to increase input conductance 15 +/- 3% above control and inhibited N-type Ca(2+) currents in 17 of 24 neurons via voltage-dependent mechanisms [12].

Biological context of Kcnj3

• The point mutation I331R in the GIRK1 C terminus or L337R in the GIRK4 C terminus decreased the association between the N and C termini [13].
• The hypothesis that similar channels play a role in neuronal inhibition is supported by the cloning of a nearly identical channel (KGB1) from a rat brain cDNA library [14].
• Assignment of the gene encoding inwardly rectifying potassium channel, subfamily J, member 3 (Kcnj3) to rat chromosome 3q32 by in situ hybridization and radiation hybrid mapping [15].
• These inhibitory effects are physiologically important in the voltage range between the resting membrane potential and the potential where voltage-gated Na+ and K+ currents are activated; that is where GIRK currents are outward [16].
• Under current clamp, GIRK activation increased the cell membrane conductance by 1- to 2-fold, hyperpolarized the cell by 11-14 mV, and inhibited action potential firing by increasing the threshold current for firing by 2- to 3-fold [16].

Anatomical context of Kcnj3

• Deletion of the GIRK1 C-terminal residues 330-384, as well as the point mutation I331R, resulted in a decrease in channel function when coexpressed with GIRK4 in oocytes and in COS-7 cells [13].
• To enable studies of the molecular mechanisms of activation, this channel, denoted KGA, was cloned from a rat atrium cDNA library by functional coupling to coexpressed serotonin type 1A receptors in Xenopus oocytes [14].
• Except for the low levels of GIRK4 transcripts observed, the overall distribution patterns of the other GIRK subunits were rather similar, with high levels of expression in the olfactory bulb, hippocampus, cortex, thalamus, and cerebellum [17].
• GIRK1 mRNA expression in the brain is widespread with highest levels in the cortex, septum, hippocampus, thalamus, amygdala, cerebellum, and many nuclei of the midbrain and hindbrain, including red nucleus, inferior colliculus, pontine nucleus, nucleus of the solitary tract, and multiple cranial nerve nuclei (motor and sensory components) [18].
• These effects were not found in non- and mock-infected neurons, and were similar to the effects of muscarinic stimulation of native GIRK currents in atrial myocytes [16].

Associations of Kcnj3 with chemical compounds

• The expressed KGA channel is activated by serotonin 1A, muscarinic m2, and delta-opioid receptors via G proteins [14].
• KGA is activated by guanosine 5'-[gamma-thio]triphosphate in excised patches, confirming activation by a membrane-delimited pathway, and displays a conductance equal to that of the endogenous channel in atrial cells [14].
• Such activation was eliminated when a histidine residue in the M1-H5 linker was mutated to a non-titratable glutamine, i.e. H116Q in GIRK1 and H120Q in GIRK4 [1].
• To investigate possible effects of adrenergic stimulation on G protein-activated inwardly rectifying K(+) channels (GIRK), acetylcholine (ACh)-evoked K(+) current, I(KACh), was recorded from adult rat atrial cardiomyocytes using the whole cell patch clamp method and a fast perfusion system [19].
• Rf-evoked GIRK currents were not altered by PTX pretreatment but were suppressed by intracellularly injected guanosine-5'-(2-O-thio) diphosphate, a nonhydrolyzable GDP analog [20].

Physical interactions of Kcnj3

• In the present study we have investigated the effect of electroconvulsive shock on gene expression of the G-protein-activated inward rectifier potassium channel subunits G-protein-coupled inward rectifier K+-channel (GIRK1) and GIRK2 in the rat brain using in situ hybridization and immunocytochemistry [4].

Regulatory relationships of Kcnj3

• Surface protein expression of GIRK1 I331R coexpressed with GIRK4 was comparable with wild type, indicating that subunits assemble and are correctly localized to the membrane [13].
• We report that the GIRK1 protein is expressed prominently in the olfactory bulb, hippocampus, dentate gyrus, neocortex, thalamus, cerebellar cortex, and several brain stem nuclei [21].
• The five different rat somatostatin receptor subtypes (SSTR1-SSTR5) were coexpressed with a subunit of G-protein gated inwardly rectifying potassium channel (GIRK1) in Xenopus oocytes [22].

Other interactions of Kcnj3

• Intracellular domain associations resulted in the coimmunoprecipitation of the GIRK1 N and C termini and GIRK4 N and C termini [13].
• As heterotetramers, they comprise the GIRK1 and the GIRK2, -3, or -4 subunits [23].
• These results indicate that Rf activates GIRK channel through an unidentified G protein-coupled receptor in rat brain and that this receptor can be cloned by the expression method demonstrated here [20].
• 7. In summary, the attachment of GFP mutants to the N-terminus of G beta 1 or G gamma 2 does not qualitatively impair their ability to form a heterotrimer, modulate effectors (N-type Ca(2+) and GIRK channels), or couple to receptors [24].
• The subcellular localization of GIRK1-IR in the Golgi apparatus of pyramidal cell somata and in the plasma membrane of dendrites and dendritic spines confirms the hypothesis that GIRK1 is synthesized by pyramidal cells and transported to the more distal dendritic processes [25].

Analytical, diagnostic and therapeutic context of Kcnj3

• We have used in situ hybridization histochemistry to characterize the pattern of expression of GIRK1 mRNA in adult rat heart and brain [18].
• Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and nucleus basalis neurons [26].
• Whole-cell recordings of EPSCs and G-protein-activated inwardly rectifying (GIRK) currents were made from cultured hippocampal neurones to determine the effect of long-term agonist treatment on the presynaptic and postsynaptic responses mediated by GABA(B) receptors (GABA(B)Rs) [27].
• 1. G protein-gated inwardly rectifying K+ (GIRK) channels were heterologously expressed in rat superior cervical ganglion (SCG) neurons by intranuclear microinjection [10].
• 1. G protein-regulated inward rectifier K+ (GIRK) channels were over-expressed in dissociated rat superior cervical sympathetic (SCG) neurones by co-transfecting green fluorescent protein (GFP)-, GIRK1- and GIRK2-expressing plasmids using the biolistic technique [28].

References