Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002962 (angina)
 21,142 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ATP-sensitive K+ (KATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of KATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native KATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K+ channel-opening drugs (KCOs). Although these characteristics can be shared with KATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of KATP channels. For example, native KATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K+ channel (Kir) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the Kir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of KATP channels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: Kir6.2 with SUR1 (SUR1/Kir6.2, pancreatic type), Kir6.2 with SUR2A (SUR2A/ Kir6.2, cardiac type), and Kir6.1 with SUR2B (SUR2B/Kir6.1, VSM type) [i.e., (SUR/Kir6.x)4]. It remains to be determined what are the molecular connections between the SUR and Kir subunits that enable this unique complex to work as a functional KATP channel.
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PMID:ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. 945 9

The inwardly rectifying K(+) channel Kir6.1 forms K(+) channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K(+) channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudden death associated with spontaneous ST elevation followed by atrioventricular block as seen on an electrocardiogram. The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil. The administration of methylergometrine, a vasoconstrictive agent, elicited ST elevation followed by cardiac death in Kir6.1-null mice but not in wild-type mice, indicating a phenotype characterized by hypercontractility of coronary arteries and resembling Prinzmetal (or variant) angina in humans. The Kir6.1-containing K(+) channel is critical in the regulation of vascular tonus, especially in the coronary arteries, and its disruption may cause Prinzmetal angina.
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PMID:Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. 1198 90

The disturbances in coronary vasomotor tone have been extensively analyzed, but the exact molecular mechanisms underlying abnormal coronary vasomotion remain to be elucidated. It has been suggested that impaired coronary vasoreactivity can be the expression of a defect in vascular smooth muscle cells. A mouse model of human variant (vasospastic) angina has been recently obtained by disruption of Kir6.1/Kcnj8, a gene coding for a small pore-forming inward rectifier potassium channel. A phenotype resembling variant angina was also reported in mice lacking Sur2, the partner protein of Kir6.1. To better define the role of the smooth muscular ATP-sensitive potassium channels in the pathogenesis of abnormal coronary vasomotion, a complete mutational analysis of Kir6.1/KCNJ8 gene was performed in a series of 18 Italian patients with impaired coronary vasomotility. Polymerase chain reaction and direct sequencing of PCR products were done. No mutations were detected in the sample analyzed, thus suggesting that Kir6.1/KCNJ8 aberrations are not a common cause of abnormal coronary vasomotion in Italians. To the best of our knowledge, this study represents the first mutational analysis of Kir6.1/KCNJ8 gene in humans. Since major racial differences in the prevalence of abnormal coronary vasomotion have been described, further mutation screenings of Kir6.1/KCNJ8 gene are required to assess its role in the pathogenesis of impaired coronary vasomotility among various ethnic groups.
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PMID:Absence of Kir6.1/KCNJ8 mutations in Italian patients with abnormal coronary vasomotion. 1296 27

Physiological and pathophysiological roles of K(ATP) channels have been clarified recently in genetically engineered mice. The Kir6.2-containing K(ATP) channels in pancreatic ss-cells and the hypothalamus are essential in the regulation of glucose-induced insulin secretion and hypoglycemia-induced glucagon secretion, respectively, and are involved in glucose uptake in skeletal muscles, thus playing a key role in the maintenance of glucose homeostasis. Disruption of Kir6.1-containing K(ATP) channels in mice leads to spontaneous vascular spasm mimicking vasospastic (Prinzmetal) angina in humans, indicating that the Kir6.1-containing K(ATP) channels in vascular smooth muscles participate in the regulation of vascular tonus, especially in coronary arteries. Together with protective roles of K(ATP) channels against cardiac ischemia and hypoxia-induced seizure propagation, it is now clear that K(ATP) channels, as metabolic sensors, are critical in the maintenance of homeostasis against acute metabolic changes.
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PMID:Roles of KATP channels as metabolic sensors in acute metabolic changes. 1591 Aug 76

The etiology of coronary spastic angina (CSA) remains uncertain. Mice lacking the gene encoding the inwardly rectifying K(+) channel Kir6.1 were developed as an animal model of CSA. We investigated whether mutation in the coding region of the Kir6.1 gene is detected in Japanese patients with CSA. The study population included 19 Japanese patients with CSA (10 men and 9 women with a mean age of 61+/-14 years). Mutational analysis of the coding region of Kir6.1 was performed by direct sequencing. We found no missense or nonsense mutations in these samples, but we found in one female CSA patient, a single base substitution (C to T) at nucleotide position 111 in exon 2 of the coding region, which was heterozygous and did not cause amino acid substitution (Ile37Ile, silent mutation). In the remaining 18 patients, no base substitution was detected in the coding region of the Kir6.1 gene. No mutation that alters primary structure of Kir6.1 was detected in Japanese patients with CSA. The results indicate that abnormality in the primary structure of Kir6.1 may not be involved in the genetic pathogenesis of CSA in humans.
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PMID:Mutational analysis of Kir6.1 in Japanese patients with coronary spastic angina. 1696 9

Vascular ATP-sensitive K(+) (K(ATP)) channels are critical regulators of arterial tone and, thus, blood flow in response to local metabolic needs. They are important targets for clinically used drugs to treat hypertensive emergency and angina. It is known that protein kinase C (PKC) activation inhibits K(ATP) channels in vascular smooth muscles. However, the mechanism by which PKC inhibits the channel remains unknown. Here we report that caveolin-dependent internalization is involved in PKC-epsilon-mediated inhibition of vascular K(ATP) channels (Kir6.1 and SUR2B) by phorbol 12-myristate 13-acetate or angiotensin II in human embryonic kidney 293 cells and human dermal vascular smooth muscle cells. We showed that Kir6.1 substantially overlapped with caveolin-1 at the cell surface. Cholesterol depletion with methyl-beta-cyclodextrin significantly reduced, whereas overexpression of caveolin-1 largely enhanced, PKC-induced inhibition of Kir6.1/SUR2B currents. Importantly, we demonstrated that activation of PKC-epsilon caused internalization of K(ATP) channels, the effect that was blocked by depletion of cholesterol with methyl-beta-cyclodextrin, expression of dominant-negative dynamin mutant K44E, or knockdown of caveolin-1 with small interfering RNA. Moreover, patch-clamp studies revealed that PKC-epsilon-mediated inhibition of the K(ATP) current induced by PMA or angiotensin II was reduced by a dynamin mutant, as well as small interfering RNA targeting caveolin-1. The reduction in the number of plasma membrane K(ATP) channels by PKC activation was further confirmed by cell surface biotinylation. These studies identify a novel mechanism by which the levels of vascular K(ATP) channels could be rapidly downregulated by internalization. This finding provides a novel mechanistic insight into how K(ATP) channels are regulated in vascular smooth muscle cells.
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PMID:Protein kinase C-epsilon induces caveolin-dependent internalization of vascular adenosine 5'-triphosphate-sensitive K+ channels. 1866 57