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PubMed1999

Direct block of native and cloned (Kir2.1) inward rectifier K+ channels by chloroethylclonidine.

1. We have investigated the inhibition of inwardly rectifying potassium channels by the alpha-adrenergic agonist/antagonist chloroethylclonidine (CEC). We used two preparations; two-electrode voltage-clamp of rat isolated flexor digitorum brevis muscle and whole-cell patch-clamp of cell lines transfected with Kir2.1 (IRK1). 2. In skeletal muscle and at a membrane potential of -50 mV, chloroethylclonidine (CEC), an agonist at alpha2-adrenergic receptors and an antagonist at alpha1x-receptors, was found to inhibit the inward rectifier current with a Ki of 30 microM. 3. The inhibition of skeletal muscle inward rectifier current by CEC was not mimicked by clonidine, adrenaline or noradrenaline and was not sensitive to high concentrations of alpha1-(prazosin) or alpha2-(rauwolscine) antagonists. 4. The degree of current inhibition by CEC was found to vary with the membrane potential (approximately 70% block at -50 mV c.f. approximately 10% block at -190 mV). The kinetics of this voltage dependence were further investigated using recombinant inward rectifier K+ channels (Kir2.1) expressed in the MEL cell line. Using a two pulse protocol, we calculated the time constant for block to be approximately 8 s at 0 mV, and the rate of unblock was described by the relationship tau=exp((Vm+149)/22) s. 5. This block was effective when CEC was applied to either the inside or the outside of patch clamped cells, but ineffective when a polyamine binding site (aspartate 172) was mutated to asparagine. 6. The data suggest that the clonidine-like imidazoline compound, CEC, inhibits inward rectifier K+ channels independently of alpha-receptors by directly blocking the channel pore, possibly at an intracellular polyamine binding site.

Animals↗

PubMed2005

Carvedilol blocks cardiac KATP and KG but not IK1 channels by acting at the bundle-crossing regions.

We examined the effects of carvedilol on cardiac inwardly rectifying K(+) (Kir) channels, i.e., ATP-sensitive (K(ATP)), G-protein-activated (K(G)) and background (I(K1)) Kir channels. We found that carvedilol effectively inhibits K(ATP) and K(G), but not I(K1) channels. Carvedilol inhibits K(ATP) channels reconstituted in HEK293 cells with Kir6.2 lacking the C-terminal 26 amino acids (Kir6.2DeltaC26), suggesting that carvedilol acts in the channel pore. A sequence comparison of the three channels revealed that a cysteine residue, C166, in the inner helix of Kir6.2 is conserved in both Kir6.xs (K(ATP)) and Kir3.xs (K(G)), but not in Kir2.xs (I(K1)). The mutation of this residue (C166A) made Kir6.2DeltaC26 resistant to the drug. Homology modeling and docking simulation suggested that interaction between carvedilol and the pore could be located at the cytosolic portion of the inner helix (bundle-crossing region) containing C166. This study shows that carvedilol blocks specific groups of Kir channels by interacting with the bundle-crossing region.

Amino Acid Sequence↗

PubMed1994

Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits.

Acetylcholine released during parasympathetic stimulation of the vagal nerve slows the heart rate through the activation of muscarinic receptors and subsequent opening of an inwardly rectifying potassium channel. The activation of these muscarinic potassium channels is mediated by a pertussis toxin-sensitive heterotrimeric GTP-binding protein (G protein). It has not been resolved whether exogenously applied G alpha or G beta gamma, or both, activate the channel. Using a heterologous expression system, we have tested the ability of different G protein subunits to activate the cloned muscarinic potassium channel, GIRK1. We report here that coexpression of GIRK1 with G beta gamma but not G alpha beta gamma in Xenopus oocytes results in channel activity that persists in the absence of cytoplasmic GTP. This activity is reduced by fusion proteins of the beta-adrenergic receptor kinase and of recombinant G alpha i-GDP, both of which are known to interact with G beta gamma. Moreover, application of recombinant G beta gamma, but not G alpha i-GTP-gamma S, activates GIRK1 channels. Thus G beta gamma appears to be sufficient for the activation of GIRK1 muscarinic potassium channels.

Amino Acid Sequence↗

PubMed2004

K+ activation of kir3.1/kir3.4 and kv1.4 K+ channels is regulated by extracellular charges.

K+ activates many inward rectifier and voltage-gated K+ channels. In each case, an increase in K+ current through the channel can occur despite a reduced driving force. We have investigated the molecular mechanism of K+ activation of the inward rectifier K+ channel, Kir3.1/Kir3.4, and the voltage-gated K+ channel, Kv1.4. In the Kir3.1/Kir3.4 channel, mutation of an extracellular arginine residue, R155, in the Kir3.4 subunit markedly reduced K+ activation of the channel. The same mutation also abolished Mg2+ block of the channel. Mutation of the equivalent residue in Kv1.4 (K532) abolished K+ activation as well as C-type inactivation of the Kv1.4 channel. Thus, whereas C-type inactivation is a collapse of the selectivity filter, K+ activation could be an opening of the selectivity filter. K+ activation of the Kv1.4 channel was enhanced by acidic pH. Mutation of an extracellular histidine residue, H508, that mediates the inhibitory effect of protons on Kv1.4 current, abolished both K+ activation and the enhancement of K+ activation at acidic pH. These results suggest that the extracellular positive charges in both the Kir3.1/Kir3.4 and the Kv1.4 channels act as "guards" and regulate access of K+ to the selectivity filter and, thus, the open probability of the selectivity filter. Furthermore, these data suggest that, at acidic pH, protonation of H508 inhibits current through the Kv1.4 channel by decreasing K+ access to the selectivity filter, thus favoring the collapse of the selectivity filter.

Animals↗

PubMed2003

Nuclear immunostaining in rat neuronal cells using two anti-Kir2.2 ion channel polyclonal antibodies.

The inwardly rectifying potassium ion channel Kir2.2 has recently been demonstrated to have nuclear and plasma membrane subcellular localization. Nuclear expression of Kir2.2 is controversial, as a functional role for Kir2.0 potassium channels in the nucleus has not been investigated. However, in this report we have demonstrated Kir2.2 nuclear localization in sections of rat hindbrain and dorsal root ganglia tissue, using two anti- Kir2.2 polyclonal antisera with different epitope specificities. These data confirm nuclear localization and are suggestive of new functions of Kir2.0 potassium ion channels in the nucleus.

Animals↗

PubMed2001

Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels.

BACKGROUND: General anesthetics differentially affect various families of potassium channels, and some potassium channels are suggested to be potential targets for anesthetics and alcohols. METHODS: The voltage-gated (ERG1, ELK1, and KCNQ2/3) and inwardly rectifying (GIRK1/2, GIRK1/4, GIRK2, IRK1, and ROMK1) potassium channels were expressed in Xenopus oocytes. Effects of volatile agents [halothane, isoflurane, enflurane, F3 (1-chloro-1,2,2-trifluorocyclobutane), and the structurally related nonimmobilizer F6 (1,2-dichlorohexafluorocyclobutane)], as well as intravenous (pentobarbital, propofol, etomidate, alphaxalone, ketamine), and gaseous (nitrous oxide) anesthetics and alcohols (ethanol and hexanol) on channel function were studied using a two-electrode voltage clamp. RESULTS: ERG1, ELK1, and KCNQ2/3 channels were either inhibited slightly or unaffected by concentrations corresponding to twice the minimum alveolar concentrations or twice the anesthetic EC50 of volatile and intravenous anesthetics and alcohols. In contrast, G protein-coupled inwardly rectifying potassium (GIRK) channels were inhibited by volatile anesthetics but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 minimum alveolar concentrations of halothane or F3 by 45 and 81%, respectively, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by mu-opioid receptors were also inhibited by halothane. Nitrous oxide (approximately 0.6 atmosphere) slightly but selectively potentiated GIRK channels. Results of chimeric and multiple amino acid mutations suggest that the region containing the transmembrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels. CONCLUSIONS: G protein-coupled inwardly rectifying potassium channels, especially those composed of GIRK2 subunits, were inhibited by clinical concentrations of volatile anesthetics. This action may be related to some side effects of these agents.

Amino Acid Sequence↗

PubMed1987

Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions.

The mechanism of rectification of the inwardly rectifying potassium channel was examined with single-channel recording techniques in isolated ventricular myocytes from adult guinea pig heart. Inward, or anomalous, rectification describes the property that potassium (K) current can enter the cell at potentials negative to the potassium equilibrium potential, EK, more readily than it can leave the cell at positive potentials. Voltage ramps applied to single inward rectifier channels in cell-attached patches produced single-channel currents that rectified strongly with a marked reduction in current at a potential near EK. At more positive potentials no current could be detected. Rectification was influenced by external and internal K concentrations. Single-channel activity, which usually disappears rapidly in excised patches, could be maintained by removing calcium from the internal solution. Rectification could be eliminated by excision of the patch into an internal solution in which free magnesium (Mg2+) was reduced to less than 1 microM, and it could be restored by the addition of approximately 1 mM Mg2+ to the internal solution. At intermediate concentrations of Mg2+, intermediate degrees of rectification were obtained, and the current at potentials positive to EK was often interrupted by brief closures. These studies suggest that rectification is due to internal block by Mg2+, possibly the result of rapid block of the open channel.

Animals↗

PubMed1998

Interaction of permeant and blocking ions in cloned inward-rectifier K+ channels.

Blocking cloned inward-rectifier potassium (Kir) channels from the cytoplasmic side was analyzed with a rapid application system exchanging the intracellular solution on giant inside-out patches from Xenopus oocytes in <2 ms. Dependence of the pore-block on interaction of the blocking molecule with permeant and impermeant ions on either side of the membrane was investigated in Kir1.1 (ROMK1) channels blocked by ammonium derivatives and in Kir4.1 (BIR10) channels blocked by spermine. The blocking reaction in both systems showed first-order kinetics and allowed separate determination of on- and off-rates. The off-rates of block were strongly dependent on the concentration of internal and external bulk ions, but almost independent of the ion species at the cytoplasmic side of the membrane. With K+ as the only cation on both sides of the membrane, off-rates exhibited strong coupling to the K+ reversal potential (E(K)) and increased and decreased with reduction in intra and extracellular K+ concentration, respectively. The on-rates showed significant dependence on concentration and species of internal bulk ions. This control of rate-constants by interaction of permeant and impermeant internal and external ions governs the steady-state current-voltage relation (I-V) of Kir channels and determines their physiological function under various conditions.

Animals↗

PubMed1997

Two-sided action of protons on an inward rectifier K+ channel (IRK1).

A cloned inwardly rectifying potassium channel, IRK1, expressed in Xenopus oocytes was found to be sensitive to an extracellular acidic pH level of below 6, achieved by buffering with a membrane-impermeable buffer, phthalate. The voltage dependency of the suppressive effect of pH on the macroscopic current suggested that the location of the proton-sensitive site was at approximately 5% of the distance from the outer entrance to the pore. The single-channel conductance was reduced by protonation of the channel on the extracellular side. The external proton-binding site appears to consist of a single class of negatively charged groups with a pK of around 4.6. An intracellular acidic pH, buffered with membrane-permeable acetate, was found to inhibit, in a voltage-independent manner, the macroscopic IRK1 current with an approximate apparent pK of 5.6 and an approximate apparent Hill coefficient of 2.3. The single-channel activity was abolished by intracellular acidification down to pH 5.0.

Animals↗

PubMed1995

Barium inhibits the endothelium-dependent component of flow but not acetylcholine-induced relaxation in isolated rabbit cerebral arteries.

An increase in blood flow can cause vasodilation through a local action on the blood vessel wall. We examined the involvement of potassium channels in the relaxation of segments of the rabbit middle cerebral artery to intraluminal infusion of physiological saline. In segments with intact endothelium, intraluminal flow (20 microliters/min) produced a relaxation of 81.7 +/- 3.0% of pre-flow tone. This relaxation was significantly reduced upon endothelium removal (43%, n = 5) or inhibition of nitric oxide synthase (34%, n = 6). Inhibition of nitric oxide synthase had no effect on the relaxation in endothelium denuded preparations. This suggests that the overall response to flow is a combination of endothelium/nitric oxide dependent and smooth muscle components. Barium chloride (10 and 300 microM) reduced flow-induced relaxations by 30 and 61%, respectively, in intact arteries but had no effect following endothelium removal or nitric oxide synthase inhibition. Micromolar concentrations of barium are thought to block selectively the inward rectifier potassium channel. These concentrations of barium were without effect on the relaxation produced by the endothelium-dependent vasodilator acetylcholine. Blockers of other potassium channels, glibenclamide (10 microM, ATP-sensitive K+ channel), charybdotoxin (100 nN) and tetraethylammonium (0.3 mM, Ca(++)-activated K+ channel) and 4-aminopyridine (1 mM, delayed rectifier K+ channel) did not effect either endothelium-dependent or endothelium-independent flow-induced relaxation. Our results suggest that flow-induced shear stress activates endothelial cell inward rectifier potassium channels leading to increased synthesis/release of nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed2002

Structural characterization of the mouse Girk genes.

Cardiac and neuronal G protein-gated potassium (K(G)) channels are activated by neurotransmitters such as acetylcholine, opioids, and dopamine. K(G) channel activation leads to an inhibition of synaptic transmission. K(G) channels are tetrameric complexes formed by assembly of G protein-gated, inwardly-rectifying potassium (K(+)) channel (GIRK) subunits. Four mammalian GIRK subunits (GIRK1-4) have been identified. In this study, we identify key features of the four mouse Girk genes including sequence, intron/exon structures, alternative splicing events, and candidate transcriptional start points. The mouse Girk genes are organized similarly, each containing four to seven exons. While the mouse Girk1 and Girk2 genes are relatively large (>100 kb), mouse Girk3 and Girk4 genes are compact (<20 kb). Multiple mRNA variants of Girk1, Girk3, and Girk4 were identified, existing by virtue of alternative splicing and/or usage of distinct transcription initiation sites. These findings should facilitate future studies aimed at understanding the transcriptional regulation of K(G) channels and their potential involvement in disease.

Alternative Splicing↗

PubMed2003

Short-term desensitization of G-protein-activated, inwardly rectifying K+ (GIRK) currents in pyramidal neurons of rat neocortex.

Whole cell recordings from acutely isolated rat neocortical pyramidal cells were performed to study the kinetics and the mechanisms of short-term desensitization of G-protein-activated, inwardly rectifying K+ (GIRK) currents during prolonged application (5 min) of baclofen, adenosine, or serotonin. Most commonly, desensitization of GIRK currents was characterized by a biphasic time course with average time constants for fast and slow desensitization in the range of 8 and 120 s, respectively. The time constants were independent of the agonist used to evoke the current. The biphasic time course was preserved in perforated-patch recordings, indicating that neither component of desensitization is attributable to cell dialysis. Desensitization of GIRK currents displayed a strong heterologous component in that application of a second agonist substantially reduced the responsiveness to a test agonist. Fast desensitization, but not slow desensitization, was lost in cells loaded with GDP, suggesting that the hydrolysis cycle of G proteins might underlie the initial, rapid current decline. Hydrolysis of phosphatidylinositol biphosphate is an unlikely candidate underlying short-term desensitization, because both components of desensitization were preserved in the presence of the phospholipase C inhibitor U73122. We conclude that short-term desensitization does neither result from receptor downregulation nor from altered channel gating but might involve modifications of the G-protein-dependent pathway that serves to translate receptor activation into channel opening.

Action Potentials↗

PubMed2004

The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via alpha-syntrophin in glia.

One of the major physiological roles of potassium channels in glial cells is to promote "potassium spatial buffering" in the central nervous system, a process necessary to maintain an optimal potassium concentration in the extracellular environment. This process requires the precise distribution of potassium channels accumulated at high density in discrete subdomains of glial cell membranes. To obtain a better understanding of how glial cells selectively target potassium channels to discrete membrane subdomains, we addressed the question of whether the glial inwardly rectifying potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex (DGC). Immunoprecipitation experiments revealed that Kir4.1 is associated with the DGC in mouse brain and cultured cortical astrocytes. In vitro immunoprecipitation and pull-down assays demonstrated that Kir4.1 can bind directly to alpha-syntrophin, requiring the presence of the last three amino acids of the channel (SNV), a consensus PDZ domain-binding motif. Furthermore, Kir4.1 failed to associate with the DGC in brains from alpha-syntrophin knockout mice. These results suggest that Kir4.1 is localized in glial cells by its association with the DGC through a PDZ domain-mediated interaction with alpha-syntrophin and suggest an important role for the DGC in central nervous system physiology.

Animals↗

PubMed2001

Regulated expression of adenosine triphosphate-sensitive potassium channel subunits in pancreatic beta-cells.

The regulation of glucose-dependent insulin secretion in pancreatic beta-cells is linked to the expression and function of the ATP-sensitive potassium channel (K(ATP)), which is composed of a sulfonylurea receptor (SUR1) and an inwardly rectifying potassium channel (Kir6.2). Previous animal and human genetic studies have demonstrated that disruption or defective expression of K(ATP) subunit genes has a profound impact on the regulation of insulin secretion. Little is known about how SUR1 and Kir6.2 gene expression is regulated. Here we show that high glucose concentrations lead to a marked decrease (approximately 70%) in Kir6.2 messenger RNA (mRNA) levels in isolated rat pancreatic islets as well as in the INS-1 beta-cell line. This effect is reversible, because exposure to low glucose reinduces Kir6.2 transcript levels. The cognate K(ATP) channel subunit SUR1 showed similar down-regulation at high glucose concentration. The K(ATP) channel activity of INS-1 cells cultivated at high glucose was reduced by 33-51%. In contrast, glucagon-like peptide-1 (GLP-1) induced Kir6.2 mRNA steady state levels and was able to prevent glucose-dependent inhibition of Kir6.2 mRNA and K(ATP) channel activity. To provide further insight into the mechanisms by which glucose and GLP-1 regulate beta-cell K(ATP) channel genes, we have cloned and initiated the characterization of the Kir6.2 gene transcriptional regulatory regions contained within the entire 4.5 kb flanked by the SUR1 and Kir6.2 genes. Transient transfection experiments with five deletion constructs in a pancreatic beta-cell line (INS-1) showed that the proximal 988 bp of the Kir6.2 promoter sequence contributes only 25-30% to the total basal promoter activity. The minimal promoter region -67/+140, also encompassing parts of the 5'-untranslated region, confers sensitivity to GLP-1, which stimulates transcriptional activity of the Kir6.2 minigene by about 2-fold. We propose that glucose- and GLP-1-dependent regulation of K(ATP) subunit genes may be important in the adaptation of beta-cells to changes in secretory demands in physiological and diseased states.

ATP-Binding Cassette Transporters↗

PubMed2003

Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice.

Multiple G protein-linked neurotransmitter systems have been implicated in the behavioral effects of cocaine. While actions of certain neurotransmitter receptor subtypes and transporters have been identified, the role of individual G protein-regulated enzymes and ion channels in the effects of cocaine remains unclear. Here, we assessed the contribution of G protein-gated, inwardly rectifying potassium (Kir3/GIRK) channels to the locomotor-stimulatory and reinforcing effects of cocaine using knockout mice lacking one or both of the key neuronal channel subunits, Kir3.2 and Kir3.3. Cocaine-stimulated increases in horizontal locomotor activity in wild-type, Kir3.2 knockout, Kir3.3 knockout, and Kir3.2/3.3 double knockout mice, with only minor differences observed between the mouse lines. In contrast, Kir3.2 and Kir3.3 knockout mice exhibited dramatically reduced intravenous self-administration of cocaine relative to wild-type mice over a range of cocaine doses. Paradoxically, Kir3.2/3.3 double knockout mice self-administered cocaine at levels significantly higher than either single knockout alone. These findings suggest that Kir3 channels play significant and complex roles in the reinforcing effect of cocaine.

Animals↗

PubMed2004

Inhibition of ATP-sensitive K+ channels by taurine through a benzamido-binding site on sulfonylurea receptor 1.

ATP-sensitive potassium (K(ATP)) channels in pancreatic beta-cells comprise sulfonylurea receptor (SUR) 1 and inwardly-rectifying potassium channel (Kir) 6.2 subunits. We have evaluated the effect of intracellular taurine on K(ATP) channel activity in rat pancreatic beta-cells using the patch-clamp technique. The mechanism of taurine action was also examined using recombinant K(ATP) channels. The islets and single beta-cells from male Sprague-Dawley rats were collected by collagenase digestion technique. Single K(ATP) channel currents were recorded by the inside-out mode at a membrane potential of -60mV. Cytosolic free-Ca(2+) concentration ([Ca(2+)](c)) and insulin secretory capacity were measured by the dual-excitation fluorimetry and radioimmunoassay, respectively. The native beta-cell K(ATP) channel was directly inhibited by taurine in a dose-dependent manner. Taurine did not influence ATP-mediated inhibition or MgADP-induced activation of the channel activity. The sensitivity of the K(ATP) channel to glybenclamide, but not gliclazide, was enhanced by taurine. Glybenclamide elicited a greater increase in [Ca(2+)](c) and increased insulin secretion in the beta-cells when pretreated with taurine. Taurine did not inhibit Kir6.2DeltaC36 currents, a truncated form of Kir6.2, expressed in Xenopus oocytes without SUR. These results demonstrate that taurine inhibits the K(ATP) channel activity in the beta-cells, interacting with a benzamido-binding site on SUR1, but not Kir6.2.

Adenosine Diphosphate↗

PubMed2006

Activating mutations in the ABCC8 gene in neonatal diabetes mellitus.

BACKGROUND: The ATP-sensitive potassium (K(ATP)) channel, composed of the beta-cell proteins sulfonylurea receptor (SUR1) and inward-rectifying potassium channel subunit Kir6.2, is a key regulator of insulin release. It is inhibited by the binding of adenine nucleotides to subunit Kir6.2, which closes the channel, and activated by nucleotide binding or hydrolysis on SUR1, which opens the channel. The balance of these opposing actions determines the low open-channel probability, P(O), which controls the excitability of pancreatic beta cells. We hypothesized that activating mutations in ABCC8, which encodes SUR1, cause neonatal diabetes. METHODS: We screened the 39 exons of ABCC8 in 34 patients with permanent or transient neonatal diabetes of unknown origin. We assayed the electrophysiologic activity of mutant and wild-type K(ATP) channels. RESULTS: We identified seven missense mutations in nine patients. Four mutations were familial and showed vertical transmission with neonatal and adult-onset diabetes; the remaining mutations were not transmitted and not found in more than 300 patients without diabetes or with early-onset diabetes of similar genetic background. Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had a markedly higher P(O) than did wild-type channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. CONCLUSIONS: Dominant mutations in ABCC8 accounted for 12 percent of cases of neonatal diabetes in the study group. Diabetes results from a newly discovered mechanism whereby the basal magnesium-nucleotide-dependent stimulatory action of SUR1 on the Kir pore is elevated and blockade by sulfonylureas is preserved.

ATP-Binding Cassette Transporters↗

PubMed2005

Prednisolone-induced changes in dystrophic skeletal muscle.

Although glucocorticoids delay the progression of Duchenne muscular dystrophy (DMD) their mechanism of action is unknown. Skeletal muscle gene expression profiles of mdx mice, an animal model of DMD, treated with prednisolone were compared with control mice at 1 and 6 wk. Of the 89 early differentially regulated genes and ESTs, delta-sarcoglycan, myosin Va, FK506-binding protein 51 (FKBP51), the potassium channel regulator potassium inwardly-rectifying channel Isk-like (IRK2) and ADAM 10 were overexpressed, whereas growth hormone-releasing hormone receptor (GHRHR) and Homer-2 were underexpressed. The 58 late differentially overexpressed genes included kallikreins (13, 16, and 26), FKBP51, PI3K alpha regulatory subunit, and IGFBP6, while underexpressed genes included NeuroD and nicotinic cholinergic receptor gamma. At both time points, overexpression of a cohort of genes relating to metabolism and proteolysis was apparent, alongside the differential expression of genes relating to calcium metabolism. Treatment did not increase muscle regeneration, reduce the number of infiltrating macrophages, or alter utrophin expression or localization. However, in the treated mdx soleus muscle, the percentage of slow fibers was significantly lower compared with untreated controls after 6 wk of treatment. These results show that glucocorticoids confer their benefit to dystrophic muscle in a complex fashion, culminating in a switch to a more normal muscle fiber type.

Amyloid Precursor Protein Secretases↗