Galantamine blocks cloned Kv2.1, but not Kv1.5 potassium channels

Galantamine is a cholinesterase inhibitor (AChEI) currently used in treatment of Alzheimer's disease (AD). In the present study, the effects of galantamine on currents of cloned Kv2.1 and Kv1.5 potassium channels were investigated by using patch-clamp whole cell recording techniques. Kv2.1 and Kv1.5 were stably expressed in HEK293 cells. Galantamine blocked Kv2.1 current in a concentration-dependent manner. When depolarizing from -50 to +40 mV, the IC50 of galantamine for inhibition of Kv2.1 was 5.6 microM. Galantamine 10 microM shifted the activation curve of Kv2.1 to negative potential by 4.0 mV. At the same concentration, galantamine shifted the inactivation curve to negative potential by 25.2 mV. While Kv1.5 was not sensitive to galantamine, Kv1.5 current was not changed by galantamine at concentration of 10 microM. Our data suggest that galantamine potently blocks Kv2.1, but not Kv1.5 channels.     

Transplanting the N-terminus from Kv1.4 to Kv1.1 generates an inwardly rectifying K+ channel

A chimeric channel, 4N/1, was generated from two outwardly rectifying K+ channels by linking the N-terminal cytoplasmic domain of hKv1.4 (N terminus ball and chain of hKv1.4) with the transmembrane body of hKv1.1 (delta78N1 construct of hKv1.1). The recombinant channel has properties similar to the six transmembrane inward rectifiers and opens on hyperpolarization with a threshold of activation at -90 mV. Outward currents are seen on depolarization provided the channel is first exposed to a hyperpolarizing pulse of -100 mV or more. Hyperpolarization at and beyond -130 mV provides evidence of channel deactivation. Delta78N1 does not show inward currents on hyperpolarization but does open on depolarizing from -80 mV with characteristics similar to native hKv1.1. The outward currents seen in both delta78N1 and 4N/1 inactivate slowly at rates consistent with C-type inactivation. The inward rectification of the 4N/1 chimera is consistent with the inactivation gating mechanism. This implies that the addition of the N-terminus from hKv1.4 to hKv1.1 shifts channel activation to hyperpolarizing potentials. These results suggest a mechanism involving the N-terminal cytoplasmic domain for conversion of outward rectifiers to inward rectifiers.     

Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing

Analysis of the Kv3 subfamily of K(+) channel subunits has lead to the discovery of a new class of neuronal voltage-gated K(+) channels characterized by positively shifted voltage dependencies and very fast deactivation rates. These properties are adaptations that allow these channels to produce currents that can specifically enable fast repolarization of action potentials without compromising spike initiation or height. The short spike duration and the rapid deactivation of the Kv3 currents after spike repolarization maximize the quick recovery of resting conditions after an action potential. Several neurons in the mammalian CNS have incorporated into their repertoire of voltage-dependent conductances a relatively large number of Kv3 channels to enable repetitive firing at high frequencies - an ability that crucially depends on the special properties of Kv3 channels and their impact on excitability.     

Kv3 K+ channels enable burst output in rat cerebellar Purkinje cells

The ability of cells to generate an appropriate spike output depends on a balance between membrane depolarizations and the repolarizing actions of K(+) currents. The high-voltage-activated Kv3 class of K(+) channels repolarizes Na(+) spikes to maintain high frequencies of discharge. However, little is known of the ability for these K(+) channels to shape Ca(2+) spike discharge or their ability to regulate Ca(2+) spike-dependent burst output. Here we identify the role of Kv3 K(+) channels in the regulation of Na(+) and Ca(2+) spike discharge, as well as burst output, using somatic and dendritic recordings in rat cerebellar Purkinje cells. Kv3 currents pharmacologically isolated in outside-out somatic membrane patches accounted for approximately 40% of the total K(+) current, were very fast and high voltage activating, and required more than 1 s to fully inactivate. Kv3 currents were differentiated from other tetraethylammonium-sensitive currents to establish their role in Purkinje cells under physiological conditions with current-clamp recordings. Dual somatic-dendritic recordings indicated that Kv3 channels repolarize Na(+) and Ca(2+) spikes, enabling high-frequency discharge for both types of cell output. We further show that during burst output Kv3 channels act together with large-conductance Ca(2+)-activated K(+) channels to ensure an effective coupling between Ca(2+) and Na(+) spike discharge by preventing Na(+) spike inactivation. By contributing significantly to the repolarization of Na(+) and especially Ca(2+) spikes, our data reveal a novel function for Kv3 K(+) channels in the maintenance of high-frequency burst output for cerebellar Purkinje cells.     

Roles of somatic A-type K+ channels in the synaptic plasticity of hippocampal neurons

In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hippocampus and the cerebral cortices. The modulatory mechanisms of synaptic excitability that are correlated with neuronal tasks are fundamental factors for synaptic plasticity, and they are dependent on intracellular Ca²⁺-mediated signaling. In the present review, the A-type K⁺ (I _A) channel, one of the voltage-dependent cation channels, is considered as a key player in the modulation of Ca²⁺ influx through synaptic NMDA receptors and their correlated signaling pathways. The cellular functions of I _A channels indicate that they possibly play as integral parts of synaptic and somatic complexes, completing the initiation and stabilization of memory.     

Activation and modulation of neuronal K+ channels by GABA.

Although the concept of GABAB receptors was introduced only ten years ago, several actions of GABAB agonists are already well established. They cause depression of transmitter release, a decrease in voltage-dependent Ca2+ conductance and an increase in K+ conductance. It has recently been reported that GABA also changes the voltage dependence of the transient ('A' type) K+ channel. Depression of transmitter release by GABAB agonists may be caused by a decrease in Ca2+ conductance, an increase in K+ conductance or a modulation of A channels in presynaptic nerve terminals. Slow IPSPs in some neurons are generated by an increase in K+ conductance that can be blocked by GABAB antagonists and pertussis toxin. K+ channels of variable amplitude that are blocked by pertussis toxin are activated by GABAB agonists in cultured hippocampal neurons. Since arachidonic acid activates similar channels in excised patches of membrane, it may form part of a normal second messenger system linking GABAB receptors to K+ channels.     

Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels

Arachidonic acid (AA) is a free fatty acid membrane‐permeable second messenger that is liberated from cell membranes via receptor‐ and Ca²⁺‐dependent events. We have shown previously that extremely low [AA]_i (1 pm ) inhibits the postsynaptic voltage‐gated K⁺ current (I_A) in hippocampal neurons. This inhibition is blocked by some antioxidants. The somatodendritic I_A is mediated by Kv4.2 gene products, whereas presynaptic I_A is mediated by Kv1.4 channel subunits. To address the interaction of AA with these α‐subunits we studied the modulation of A‐currents in human embryonic kidney 293 cells transfected with either Kv1.4 or Kv4.2 rat cDNA, using whole‐cell voltage‐clamp recording. For both currents 1 pm [AA]_i inhibited the conductance by > 50%. In addition, AA shifted the voltage dependence of inactivation by ?9 (Kv1.4) and +6 mV (Kv4.2), respectively. Intracellular co‐application of Trolox C (10 μm ), an antioxidant vitamin E derivative, only slowed the effects of AA on amplitude. Notably, Trolox C shifted the voltage dependence of activation of Kv1.4‐mediated I_A by ?32 mV. Extracellular Trolox for > 15 min inhibited the AA effects on I_A amplitudes as well as the effect of intracellular Trolox on the voltage dependence of activation of Kv1.4‐mediated I_A. Extracellular Trolox further shifted the voltage dependence of activation for Kv4.2 by +33 mV. In conclusion, the inhibition of maximal amplitude of Kv4.2 channels by AA can explain the inhibition of somatodendritic I_A in hippocampal neurons, whereas the negative shift in the voltage dependence of inactivation apparently depends on other neuronal channel subunits. Both AA and Trolox potently modulate Kv1.4 and Kv4.2 channel α‐subunits, thereby presumably tuning presynaptic transmitter release and postsynaptic somatodendritic excitability in synaptic transmission and plasticity.     

Transient expression of A-type K channel alpha subunits Kv4.2 and Kv4.3 in rat spinal neurons during development

A-type K(+) currents (I(A)s) have been detected from the ventral horn neurons in rat spinal cord during embryonic day (E) 14 to postnatal day (P) 8 but not in adulthood. It is not known which types of neurons and which A-type K(+) channel alpha subunits express the I(A)s and what the possible function might be. Here, we examined the expression of two A-type K(+) channel alpha subunits, Kv4.2 and Kv4.3, in rat spinal cord at various developmental stages by immunohistochemistry. We found a transient expression of Kv4.2 in somatic motoneurons during E13.5-P8 with a peak around E17.5, which coincides temporally with the natural selection of motoneurons. Transient expression of Kv4.2 and Kv4.3 was also observed in the intermediate gray (IG) interneurons. During E19.5-P14, some IG interneurons express Kv4.2, some express Kv4.3 and a subset co-express Kv4.2 and Kv4.3. Peak expression of Kv4.2 and Kv4.3 in the IG interneurons was detected around P1, which coincides temporally with the developmental selection of IG interneurons. In contrast to the I(A)-expressing subunits Kv4.2 and Kv4.3, a delayed-rectifier K(+) channel alpha subunit Kv1.6 is persistently expressed in somatic motoneurons and IG interneurons. Together, these data support the hypothesis that expression of I(A)s may protect I(A)-expressing somatic motoneurons, and possibly also IG interneurons, from naturally occurring cell death during developmental selection.     

A prominent soma-dendritic distribution of Kv3.3 K+ channels in electrosensory and cerebellar neurons.

The expression pattern and subcellular distribution of a teleost homologue of the mammalian Kv3.3 potassium channel, AptKv3.3, was examined in the electrosensory lateral line lobe (ELL) and two cerebellar lobes in the hindbrain of the weakly electric gymnotiform Apteronotus leptorhynchus. AptKv3.3 expression was brain specific, with the highest level of expression in the cerebellum and 56% relative expression in the ELL. In situ hybridization revealed that AptKv3.3 mRNA was present in virtually all cell classes in the ELL as well as in the cerebellar lobes eminentia granularis pars posterior (EGp) and corpus cerebellum (CCb). Immunocytochemistry indicated a distribution of AptKv3.3 channels over the entire soma-dendritic axis of ELL pyramidal, granule, and polymorphic cells and over the soma and at least proximal dendrites (100 microm) of multipolar cells and neurons of the ventral molecular layer. AptKv3.3 immunolabel was present at the soma of cerebellar granule, golgi, eurydendroid, and CCb Purkinje cells, with an equally intense label throughout the dendrites of CCb Purkinje cells and EGp eurydendroid cells. Immunolabel was virtually absent in afferent or efferent axon tracts of the ELL but was detected on climbing fiber axons and on the axons and putative terminal boutons of CCb Purkinje cells. These data reveal a prominent soma-dendritic distribution of AptKv3.3 K+ channels in both principal output and local circuit neurons, a pattern that is distinct from the soma-axonal distribution that characterizes all other Kv3 K+ channels examined to date. The widespread distribution of AptKv3.3 immunolabel in electrosensory cells implies an important role in several aspects of signal processing.     

钾通道Kv4.2、Kv1.4在硫化氢后处理对大鼠短暂全脑缺血神经保护中的作用研究

目的研究硫氢化钠(sodium hydrosulfide,Na HS)后处理对短暂全脑缺血大鼠海马中钾通道Kv4.2和Kv1.4 mRNA表达变化的影响及其脑保护作用,从而探讨Na HS对大鼠短暂全脑缺血神经保护作用的机制。方法用4VO方法建立大鼠短暂性全脑缺血(transient global cerebral ischemia,t GCI)模型,大鼠被随机分配到3组,分别为:假手术组(sham)、t GCI组、Na HS后处理组。Na HS后处理组为t GCI之后1 d,给予大鼠腹腔注射Na HS 24μmmol/kg或者180μmmol/kg。通过尼氏染色与Neu N免疫染色确定海马神经元的死亡,通过RT-PCR方法检测海马组织Kv4.2和Kv1.4mRNA水平的表达变化。结果 (1)与t GCI组比较,在t GCI之后1 d给予24μmol/kg Na HS后处理使海马CA1区存活细胞数目显著增加,而高剂量的Na HS(180μmol/kg)后处理对t GCI大鼠海马CA1区则无明显的保护作用。(2)在Re 26 h和Re 48 h,海马组织中Kv4.2、Kv1.4的mRNA表达水平均明显低于假手术组(P<0.05)。在Re 26 h+Na HS组,kv4.2(1.24±0.08)和kv1.4(1.11±0.07)的mRNA表达水平均分别高于Re 26 h组的kv4.2(0.75±0.04)和kv1.4(0.79±0.06),差异均有显著性(P<0.05)。结论外源性Na HS可能通过上调大鼠t GCI后海马区Kv4.2和Kv1.4 mRNA的表达,从而导致膜电位超极化,降低神经元兴奋性和氧耗,继而保护神经元免受脑缺血损伤。     

Plasma gelsolin protects HIV-1 gp120-induced neuronal injury via voltage-gated K+ channel Kv2.1

Plasma gelsolin (pGSN), a secreted form of gelsolin, is constitutively expressed throughout the central nervous system (CNS). The neurons, astrocytes and oligodendrocytes are the major sources of pGSN in the CNS. It has been shown that levels of pGSN in the cerebrospinal fluid (CSF) are decreased in several neurological conditions including HIV-1-associated neurocognitive disorders (HAND). Although there is no direct evidence that a decreased level of pGSN in CSF is causally related to the pathogenesis of neurological disorders, neural cells, if lacking pGSN, are more vulnerable to cell death. To understand how GSN levels relate to neuronal injury in HAND, we studied the effects of pGSN on HIV-1 gp120-activated outward K⁺ currents in primary rat cortical neuronal cultures. Incubation of rat cortical neurons with gp120 enhanced the outward K⁺ currents induced by voltage steps and resulted in neuronal apoptosis. Treatment with pGSN suppressed the gp120-induced increase of delayed rectifier current (I_K) and reduced vulnerability to gp120-induced neuronal apoptosis. Application of Guangxitoxin-1E (GxTx), a Kv2.1 specific channel inhibitor, inhibited gp120 enhancement of I_K and associated neuronal apoptosis, similar effects to pGSN. Western blot and PCR analysis revealed gp120 exposure to up-regulate Kv2.1 channel expression, which was also inhibited by treatment with pGSN. Taken together, these results indicate pGSN protects neurons by suppressing gp120 enhancement of I_K through Kv2.1 channels and reduction of pGSN in HIV-1-infected brain may contribute to HIV-1-associated neuropathy.     

Contrasting expression of Kv4.3, an A-type K+ channel,in migrating Purkinje cells and other post-migratory cerebellar neurons

Kv4.3, an A-type K+ channel, is the only channel molecule showing anterior-posterior (A-P) compartmentalization in the granular layer of mammalian cerebellum known so far. Kv4.3 mRNA has been detected from the posterior but not anterior granular layer in adult rat cerebellum. To characterize this A-P compartmentalization further, we examined Kv4.3 protein expression in rat cerebellum by immunohistochemistry at the embryonic, early postnatal and adult stages. Specificity of the Kv4.3 antibody was confirmed by both Western blot and immunoprecipitation analysis. In adulthood, Kv4.3 was detected from the somatodendritic domain of posterior granule cells, with a restriction boundary in the vermal lobule VI extending laterally to the hemispheric crus 1 ansiform lobules. At the early postnatal stage, this A-P pattern first appeared on postnatal day 8, when significant numbers of granule cells had migrated into the posterior granular layer and started to express Kv4.3. Similar Kv4.3 expression in the somatodendritic domain of post-migratory neurons in the cerebellum was also observed in basket cells, stellate cells, a subset of GABAergic deep neurons, Lugaro cells and, probably, deep Lugaro cells. However, none of them showed A-P compartmentalization. Strikingly, we found Kv4.3 in several clusters of migrating Purkinje cells with mediolateral compartmentalization. These Purkinje cells no longer expressed Kv4.3 after completing the migration. By contrasting the expression in migrating and post-migratory neurons, our results suggest that Kv4.3 may play an important role in the development of cerebellum, as well as in the mature cerebellum.     

Modification of Kv2.1 K+ currents by the silent Kv10 subunits

Human and rat Kv10.1a and b cDNAs encode silent K+ channel pore-forming subunits that modify the electrophysiological properties of Kv2.1. These alternatively spliced variants arise by the usage of an alternative site of splicing in exon 1 producing an 11-amino acid insertion in the linker between the first and second transmembrane domains in Kv10.1b. In human, the Kv10s mRNA were detected by Northern blot in brain kidney lung and pancreas. In brain, they were expressed in cortex, hippocampus, caudate, putamen, amygdala and weakly in substantia nigra. In rat, Kv10.1 products were detected in brain and weakly in testes. In situ hybridization in rat brain shows that Kv10.1 mRNAs are expressed in cortex, olfactory cortical structures, basal ganglia/striatal structures, hippocampus and in many nuclei of the amygdala complex. The CA3 and dentate gyrus of the hippocampus present a gradient that show a progression from high level of expression in the caudo-ventro-medial area to a weak level in the dorso-rostral area. The CA1 and CA2 areas had low levels throughout the hippocampus. Several small nuclei were also labeled in the thalamus, hypothalamus, pons, midbrain, and medulla oblongata. Co-injection of Kv2.1 and Kv10.1a or b mRNAs in Xenopus oocytes produced smaller currents that in the Kv2.1 injected oocytes and a moderate reduction of the inactivation rate without any appreciable change in recovery from inactivation or voltage dependence of activation or inactivation. At higher concentration, Kv10.1a also reduces the activation rate and a more important reduction in the inactivation rate. The gene that encodes for Kv10.1 mRNAs maps to chromosome 2p22.1 in human, 6q12 in rat and 17E4 in mouse, locations consistent with the known systeny for human, rat and mouse chromosomes.     

Macrocurrents of voltage gated Na+ and K+ channels from the crayfish stretch receptor neuronal soma

Currents from the slowly adapting stretch receptor neuron of the crayfish (Pacifastacus leniusculus) were studied in a cell attached configuration using patch pipettes with an opening diameter of 2-10 microm. The neuronal membrane was enzymatically freed from the glial layer. The voltage gated Na+ and K+ channels seemed to be more concentrated in the lower part of soma close to the axon hillock. The Na+ and K+ currents could be analysed by fitting the currents to a fourth-order exponential function for Na+ current and a second-order exponential function for the K+ current. The macropatch recordings of enzymatically treated neurons are superior to two electrode voltage clamp recordings when analyzing voltage gated Na+ and K+ currents.     

Abnormal axonal physiology is associated with altered expression and distribution of Kv1.1 and Kv1.2 K+ channels after chronic spinal cord injury

Dysfunction of surviving axons which traverse the site of spinal cord injury (SCI) has been linked to altered sensitivity to the K+ channel blocker 4-aminopyridine (4-AP) and appears to contribute to post-traumatic neurological deficits although the underlying mechanisms remain unclear. In this study, sucrose gap electrophysiology in isolated dorsal column strips, Western blotting and confocal immunofluorescence microscopy were used to identify the K+ channels associated with axonal dysfunction after chronic (6-8 weeks postinjury) clip compresssion SCI of the thoracic cord at T7 in rats. The K+ channel blockers 4-AP (200 microM, 1 mM and 10 mM) and alpha-dendrotoxin (alpha-DTX, 500 nM) resulted in a significant relative increase in the amplitude and area of compound action potentials (CAP) recorded from chronically injured dorsal column axons in comparison with control noninjured preparations. In contrast, TEA (10 mM) and CsCl (2 mM) had similar effects on injured and control spinal cord axons. Western blotting and quantitative immunofluorescence microscopy showed increased expression of Kv1.1 and Kv1.2 K+ channel proteins on spinal cord axons following injury. In addition, Kv1.1 and Kv1.2 showed a dispersed staining pattern along injured axons in contrast to a paired juxtaparanodal localization in uninjured spinal cord axons. Furthermore, labelled alpha-DTX colocalized with Kv1.1 and Kv1.2 along axons. These findings suggest a novel mechanism of axonal dysfunction after SCI whereby an increased 4-AP- and alpha-DTX-sensitive K+ conductance, mediated in part by increased Kv1.1 and Kv1.2 K+ channel expression, contributes to abnormal axonal physiology in surviving axons.     

Pseudomonas fluorescens lipopolysaccharide inhibits both delayed rectifier and transient A-type K+ channels of cultured rat cerebellar granule neurons

Pseudomonas fluorescens is a Gram-negative bacillus closely related to the pathogen P. aeruginosa known to provoke infectious disorders in the central nervous system (CNS). The endotoxin lipopolysaccharide (LPS) expressed by the bacteria is the first infectious factor that can interact with the plasma membrane of host cells. In the present study, LPS extracted from P. fluorescens MF37 was examined for its actions on delayed rectifier and A-type K(+) channels, two of the main types of voltage-activated K(+) channels involved in the action potential firing. Current recordings were performed in cultured rat cerebellar granule neurons at days 7 or 8, using the whole-cell patch-clamp technique. A 3-h incubation with LPS (200 ng/ml) markedly depressed both the delayed rectifier (I(KV)) and transient A-type (I(A)) K(+) currents evoked by depolarizations above 0 and -40 mV, respectively. The percent decrease of I(KV) and I(A) ( approximately 30%) did not vary with membrane potential, suggesting that inhibition of both types of K(+) channels by LPS was voltage-insensitive. The endotoxin did neither modify the steady-state voltage-dependent activation properties of I(KV) and I(A) nor the steady-state inactivation of I(A). The present results suggest that, by inhibiting I(KV) and I(A), LPS applied extracellulary increases the action potential firing in cerebellar granule neurons. It is concluded that P. fluorescens MF37 may provoke in the CNS disorders associated with sever alterations of membrane ionic channel functions.     

The neuroleptic drug, fluphenazine, blocks neuronal voltage-gated sodium channels

Fluphenazine (Prolixin(R)) is a potent phenothiazine-based dopamine receptor antagonist, first introduced into clinical practice in the late 1950s as a novel antipsychotic. The drug emerged as a 'hit' during a routine ion channel screening assay, the present studies describe our electrophysiological examination of fluphenazine at tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) voltage-gated sodium channel variants expressed in three different cell populations. Constitutively expressed TTX-S conductances were studied in ND7/23 cells (a dorsal root ganglion-derived clonal cell line) and rat primary cerebrocortical neurons. Recombinant rat Na(V)1.8 currents were studied using ND7/23 cells as a host line for heterologous expression. Sodium currents were examined using standard whole-cell voltage-clamp electrophysiology. Current-voltage relationships for either ND7/23 cell or Na(V)1.8 currents revealed a prominent fluphenazine block of sodium channel activity. Steady-state inactivation curves were shifted by approximately 10 mV in the hyperpolarizing direction by fluphenazine (3 microM for ND7/23 currents and 10 microM for Na(V)1.8), suggesting that the drug stabilizes the inactivated channel state. Fluphenazine's apparent potency for blocking either ND7/23 or Na(V)1.8 sodium channels was increased by membrane depolarization, corresponding IC(50) values for the ND7/23 cell conductances were 18 microM and 960 nM at holding potentials of -120 mV and -50 mV, respectively. Frequency-dependent channel block was evident for each of the cell/channel variants, again suggesting a preferential binding to inactivated channel state(s). These experiments show fluphenazine to be capable of blocking neuronal sodium channels. Several unusual pharmacokinetic features of this drug suggest that sodium channel block may contribute to the overall clinical profile of this classical neuroleptic agent.     

The activation of G-protein gated inwardly rectifying K+ channels by a cloned Drosophila melanogaster neuropeptide F-like receptor

A Drosophila melanogaster G-protein-coupled receptor (NPFR76F) that is activated by neuropeptide F-like peptides has been expressed in Xenopus oocytes to determine its ability to regulate heterologously expressed G-protein-coupled inwardly rectifying potassium channels. The activated receptor produced inwardly rectifying potassium currents by a pertussis toxin-sensitive G-protein-mediated pathway and the effects were reduced in the presence of proteins, such as the betaARK 1 carboxy-tail fragment and alpha-transducin, which bind G-protein betagamma-subunits. Short Drosophila NPF-like peptides were more potent than long NPF-like peptides at coupling the receptor to the activation of inwardly rectifying potassium channels. The putative endogenous short Drosophila NPF-like peptides showed agonist-specific coupling depending on whether their actions were assessed as the activation of the inwardly rectifying potassium channels or as the activation of endogenous inward chloride channels through a co-expressed promiscuous G-protein, Galpha16. As inwardly rectifying potassium channels are known to be encoded in the Drosophila genome and the NPFR76F receptor is widely expressed in the Drosophila nervous system, the receptor could function to control neuronal excitability or slow wave potential generation in the Drosophila nervous system.