Nutrigenomics of inward rectifier potassium channels.

Inwardly rectifying potassium (Kir) channels play a key role in maintaining the resting membrane potential and supporting potassium homeostasis. There are many variants of Kir channels, which are usually tetramers in which the main subunit has two trans-membrane helices attached to two N- and C-terminal cytoplasmic tails with a pore-forming loop in between that contains the selectivity filter. These channels have domains that are strongly modulated by molecules present in nutrients found in different diets, such as phosphoinositols, polyamines and Mg2+. These molecules can impact these channels directly or indirectly, either allosterically by modulation of enzymes or via the regulation of channel expression. A particular type of these channels is coupled to cell metabolism and inhibited by ATP (KATP channels, essential for insulin release and for the pathogenesis of metabolic diseases like diabetes mellitus). Genomic changes in Kir channels have a significant impact on metabolism, such as conditioning the nutrients and electrolytes that an individual can take. Thus, the nutrigenomics of ion channels is an important emerging field in which we are attempting to understand how nutrients and diets can affect the activity and expression of ion channels and how genomic changes in such channels may be the basis for pathological conditions that limit nutrition and electrolyte intake. In this contribution we briefly review Kir channels, discuss their nutrigenomics, characterize how different components in the diet affect their function and expression, and suggest how their genomic changes lead to pathological phenotypes that affect diet and electrolyte intake.

Advancements in the study of inward rectifying potassium channels on vascular cells.

Inward rectifier potassium channels (Kir channels) exist in a variety of cells and are involved in maintaining resting membrane potential and signal transduction in most cells, as well as connecting metabolism and membrane excitability of body cells. It is closely related to normal physiological functions of body and the occurrence and development of some diseases. Although the functional expression of Kir channels and their role in disease have been studied, they have not been fully elucidated. In this paper, the functional expression of Kir channels in vascular endothelial cells and smooth muscle cells and their changes in disease states were reviewed, especially the recent research progress of Kir channels in stem cells was introduced, in order to have a deeper understanding of Kir channels in vascular tissues and provide new ideas and directions for the treatment of related ion channel diseases.

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels.

The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2-GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.

Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels.

Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC50 = 1.06 ± 0.11 µmol L-1) compared to Kir2.1 channels (IC50 = 27.8 ± 4.8 µmol L-1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC50 = 13.0 ± 2.9 µmol L-1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.

[Roles of G Protein-gated Inward Rectifier Potassium Channels in Substance Addiction].

G protein-gated inward rectifier potassium(GIRK)channels are widely distributed in the central nervous system and play important roles in maintaining the resting membrane potential of neurons,adjusting neuronal excitability,and regulating the release of neurotransmitter.Studies have shown that addictive behavior is closely related to the expression and activity of the GIRK channels in the brain reward system and the GIRK channels may be a potential target for addiction treatment.This article summarizes the recent research advances in GIRK channels in terms of structure,intracranial tissue distribution,and especially substance addiction.

Roles of G Protein-gated Inward Rectifier Potassium Channels in Substance Addiction / 中国医学科学院学报

G protein-gated inward rectifier potassium(GIRK)channels are widely distributed in the central nervous system and play important roles in maintaining the resting membrane potential of neurons,adjusting neuronal excitability,and regulating the release of neurotransmitter.Studies have shown that addictive behavior is closely related to the expression and activity of the GIRK channels in the brain reward system and the GIRK channels may be a potential target for addiction treatment.This article summarizes the recent research advances in GIRK channels in terms of structure,intracranial tissue distribution,and especially substance addiction.

Transcript expression of inward rectifier potassium channels of Kir2 subfamily in Arctic marine and freshwater fish species.

Inward rectifier K+ (Kir2) channels are critical for electrical excitability of cardiac myocytes. Here, we examine expression of Kir2 channels in the heart of three Gadiformes species, polar cod (Boreogadus saida) and navaga (Eleginus nawaga) of the Arctic Ocean and burbot (Lota lota) of the temperate lakes to find out the role of Kir2 channels in cardiac adaptation to cold. Five boreal freshwater species: brown trout (Salmo trutta fario), arctic char (Salvelinus alpinus), roach (Rutilus rutilus), perch (Perca fluviatilis) and pike (Esox lucius), and zebrafish (Danio rerio), were included for comparison. Transcript expression of genes encoding Kir2.1a, - 2.1b, - 2.2a, - 2.2b and - 2.4 was studied from atrium and ventricle of thermally acclimated or acclimatized fish by quantitative PCR. Kir2 composition in the polar cod was more diverse than in other species in that all Kir2 isoforms were relatively highly expressed. Kir2 composition of navaga and burbot differed from that of the polar cod as well as from those of other species. The relative expression of Kir2.2 transcripts, especially Kir2.2b, was higher in both atrium and ventricle of navaga and burbot (56-89% from the total Kir2 pool) than in other species (0.1-11%). Thermal acclimation induced only small changes in cardiac Kir2 transcript expression in Gadiformes species. However, Kir2.2b transcripts were upregulated in cold-acclimated navaga and burbot hearts. All in all, the cardiac Kir2 composition seems to be dependent on both phylogenetic position and thermal preference of the fish.

Engram Cell Excitability State Determines the Efficacy of Memory Retrieval.

Animals need to optimize the efficacy of memory retrieval to adapt to environmental circumstances for survival. The recent development of memory engram labeling technology allows a precise investigation of the processes associated with the recall of a specific memory. Here, we show that engram cell excitability is transiently increased following memory reactivation. This short-term increase of engram excitability enhances the subsequent retrieval of specific memory content in response to cues and is manifest in the animal's ability to recognize contexts more precisely and more effectively. These results reveal a hitherto unknown transient enhancement of context recognition based on the plasticity of engram cell excitability. They also suggest that recall of a contextual memory is influenced by previous but recent activation of the same engram. The state of excitability of engram cells mediates differential behavioral outcomes upon memory retrieval and may be crucial for survival by promoting adaptive behavior.

Zacopride attenuates pressure overload-induced ventricular remodeling in rats / 中国病理生理杂志

AIM:To investigate the protective effect of zacopride (ZAC) on the pressure-overload left ventricular remodeling in the rats induced by coarctation of abdominal aorta.METHODS:Male Sprague-Dawley (SD) rats with pressure overload were induced by the coarctation of abdominal aorta.The model rats were intraperitoneally administered with ZAC, chloroquine (Chlor) , and zacopride+chlorquine (ZAC+Chlor).The study duration was 8 weeks.The cardiac structure and function were assessed by echocardiography.The heart weight/body weight (HW/BW) ratio and the left ventricular weight/body weight (LVW/BW) ratio were calculated.The changes of structure and shape in myocardial tissue were observed with HE staining.The ultrastructure of the myocytes was observed under transmission electron microscope.The inward rectifier potassium channel (IK1) protein expression was determined by Western blot.The mRNA expression of Kir2.1 was detected by RT-PCR.RESULTS:Compared with vehicle group, ZAC improved cardiac function, as indicated by the decreased left ventricular end-diastolic dimension (LVEDD) and left ventricular end systolic dimension (LVESD) (P<0.05) , and the increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (P<0.01).The HW/BW and LVW/BW ratios were significantly decreased, and the cross-sectional area of the cardiomyocytes was significantly less in ZAC group than that in vehicle group (P<0.01).The ultrastructure of the myocytes was significantly improved.Chlor blocked the protective effect of zacopride on the pressure-overload left ventricular remodeling.The protein level ofmRNA expression of Kir2.1 in the cardiac tissues in ZAC group were significantly increased compared with vehicle group (P<0.01).CONCLUSION:ZAC significantly attenuates pressure overload-induced ventricular remodeling in rats.

G-protein-coupled inward rectifier potassium channels involved in corticostriatal presynaptic modulation.

Presynaptic modulation has been associated mainly with calcium channels but recent data suggests that inward rectifier potassium channels (K(IR)) also play a role. In this work we set to characterize the role of presynaptic K(IR) channels in corticostriatal synaptic transmission. We elicited synaptic potentials in striatum by stimulating cortical areas and then determined the synaptic responses of corticostriatal synapsis by using paired pulse ratio (PPR) in the presence and absence of several potassium channel blockers. Unspecific potassium channels blockers Ba(2+) and Cs(+) reduced the PPR, suggesting that these channels are presynaptically located. Further pharmacological characterization showed that application of tertiapin-Q, a specific K(IR)3 channel family blocker, also induced a reduction of PPR, suggesting that K(IR)3 channels are present at corticostriatal terminals. In contrast, exposure to Lq2, a specific K(IR)1.1 inward rectifier potassium channel, did not induce any change in PPR suggesting the absence of these channels in the presynaptic corticostriatal terminals. Our results indicate that K(IR)3 channels are functionally expressed at the corticostriatal synapses, since blockage of these channels result in PPR decrease. Our results also help to explain how synaptic activity may become sensitive to extracellular signals mediated by G-protein coupled receptors. A vast repertoire of receptors may influence neurotransmitter release in an indirect manner through regulation of K(IR)3 channels.

Phosphoinositide regulation of inward rectifier potassium (Kir) channels.

Inward rectifier potassium (Kir) channels are integral membrane proteins charged with a key role in establishing the resting membrane potential of excitable cells through selective control of the permeation of K(+) ions across cell membranes. In conjunction with secondary anionic phospholipids, members of this family are directly regulated by phosphoinositides (PIPs) in the absence of other proteins or downstream signaling pathways. Different Kir isoforms display distinct specificities for the activating PIPs but all eukaryotic Kir channels are activated by PI(4,5)P2. On the other hand, the bacterial KirBac1.1 channel is inhibited by PIPs. Recent crystal structures of eukaryotic Kir channels in apo and lipid bound forms reveal one specific binding site per subunit, formed at the interface of N- and C-terminal domains, just beyond the transmembrane segments and clearly involving some of the key residues previously identified as controlling PI(4,5)P2 sensitivity. Computational, biochemical, and biophysical approaches have attempted to address the energetic determinants of PIP binding and selectivity among Kir channel isoforms, as well as the conformational changes that trigger channel gating. Here we review our current understanding of the molecular determinants of PIP regulation of Kir channel activity, including in context with other lipid modulators, and provide further discussion on the key questions that remain to be answered.

No independent, but an interactive, role of calcium-activated potassium channels in human cutaneous active vasodilation.

In human cutaneous microvasculature, endothelium-derived hyperpolarizing factors (EDHFs) account for a large portion of vasodilation associated with local stimuli. Thus we sought to determine the role of EDHFs in active vasodilation (AVD) to passive heating in two protocols. Whole body heating was achieved using water-perfused suits (core temperature increase of 0.8-1.0°C), and skin blood flow was measured using laser-Doppler flowmetry. In the first protocol, four sites were perfused continuously via microdialysis with: 1) control; 2) tetraethylammonium (TEA) to block calcium-activated potassium (KCa) channels, and thus the actions of EDHFs; 3) N-nitro-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase (NOS); and 4) TEA + l-NAME (n = 8). Data are presented as percent maximal cutaneous vascular conductance (CVC). TEA had no effect on AVD (CVC during heated plateau: control 57.4 ± 4.9% vs. TEA 63.2 ± 5.2%, P = 0.27), indicating EDHFs are not obligatory. l-NAME attenuated plateau CVC to 33.7 ± 5.4% (P < 0.01 vs. control); while TEA + l-NAME augmented plateau CVC compared with l-NAME alone (49.7 ± 5.3%, P = 0.02). From these data, it appears combined blockade of EDHFs and NOS necessitates dilation through other means, possibly through inward rectifier (KIR) and/or ATP-sensitive (KATP) potassium channels. To test this second hypothesis, we measured AVD at the following sites (n = 8): 1) control, 2) l-NAME, 3) l-NAME + TEA, and 4) l-NAME + TEA + barium chloride (BaCl2; KIR and KATP blocker). The addition of BaCl2 to l-NAME + TEA reduced plateau CVC to 32.7 ± 6.6% (P = 0.02 vs. l-NAME + TEA), which did not differ from the l-NAME site. These data combined demonstrate a complex interplay between vasodilatory pathways, with cross-talk between NO, KCa channels, and KIR and/or KATP channels.