Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0848283 (rundown)
 502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Four cDNA-encoding G-activated inwardly rectifying K+ channels have been cloned recently (Kubo, Y., Reuveny, E., Slesinger, P. A., Jan, Y. N., and Jan, L. Y. (1993) Nature 364, 802-806; Lesage, F., Duprat, F., Fink, M., Guillemare, E., Coppola, T., Lazdunski, M., and Hugnot, J. P. (1994) FEBS Lett. 353, 37-42; Krapivinsky, G., Gordon, E. A., Wickman, K., Velimirovic, B., Krapivinsky, L., and Clapham, D. E. (1995) Nature 374, 135-141). We report the cloning of a mouse GIRK2 splice variant, noted mGIRK2A. Both channel proteins are functionally expressed in Xenopus oocytes upon injection of their cRNA, alone or in combination with the GIRK1 cRNA. Three GIRK channels, mGIRK1-3, are shown to be present in the brain. Colocalization in the same neurons of mGIRK1 and mGIRK2 supports the hypothesis that native channels are made by an heteromeric subunit assembly. GIRK3 channels have not been expressed successfully, even in the presence of the other types of subunits. However, GIRK3 chimeras with the amino- and carboxyl-terminal of GIRK2 are functionally expressed in the presence of GIRK1. The expressed mGIRK2 and mGIRK1, -2 currents are blocked by Ba2+ and Cs+ ions. They are not regulated by protein kinase A and protein kinase C. Channel activity runs down in inside-out excised patches, and ATP is required to prevent this rundown. Since the nonhydrolyzable ATP analog AMP-PCP is also active and since addition of kinases A and C as well as alkaline phosphatase does not modify the ATP effect, it is concluded that ATP hydrolysis is not required. An ATP binding process appears to be essential for maintaining a functional state of the neuronal inward rectifier K+ channel. A Na+ binding site on the cytoplasmic face of the membrane acts in synergy with the ATP binding site to stabilize channel activity.
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PMID:Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels. 749 85

1. In order to investigate the structural basis for the nucleotide-dependent gating of ATP-sensitive K+ channels (KATP), Kir6.1 (uKATP-1), Kir6.2 (BIR1) and chimeric channels were co-expressed with a common subtype of sulphonylurea receptor, SUR1, in COS7 cells. Representing the amino terminal domain-transmembrane domain-carboxyl-terminal domain of Kir6.1 as 1-1-1 and of Kir6.2 as 2-2-2, chimeric Kir6.x channels were constructed by swapping the amino and/or carboxyl terminal domains between Kir6.1 and Kir6.2 to give the chimeric x-1-x channels 1-1-2, 2-1-1 and 2-1-2, and the chimeric x-2-x channels 2-2-1, 1-2-2 and 1-2-1. 2. Inside-out patch clamp experiments revealed that both wild-type Kir6.1 and Kir6.2 formed inwardly rectifying K+ channels. Single-channel conductances were 36.3 and 66.1 pS, respectively. Chimeric x-1-x channels, whose transmembrane domain was that of Kir6.1, showed similar ion-pore properties to wild-type Kir6.1. Likewise, chimeric x-2-x channels had similar ion-pore properties to wild-type Kir6.2. 3. Wild-type Kir6.1 and Kir6.2 possessed distinct gating properties towards intracellular nucleotides. The activity of Kir6.1 was entirely dependent on Mg2+ and nucleotide diphosphates (NDPs) such as UDP. In contrast, Kir6.2 was activated upon excision of patch membrane. When Kir6.2 underwent rundown, UDP reactivated the channel. 4. In order to eliminate UDP dependence from Kir6.1, it was necessary to replace both N- and C-termini; chimera 2-1-2 opened in UDP-free conditions. With Kir6.2, substitution of the N-terminus with that of Kir6.1 conferred UDP dependence on chimeras 1-2-2 and 1-2-1. Chimera 2-2-1 opened in UDP-free conditions, but UDP potentiated the channel activity by > 20-fold. 5. The kinetics of UDP-dependent activation were significantly different between Kir6.1 and Kir6.2. Kir6.1 maximally activated by UDP was sensitive to intracellular ATP, although its ATP sensitivity was significantly lower than that of Kir6.2 measured in identical conditions. The kinetics of UDP-dependent activation and ATP sensitivity could be transferred between Kir6.1 and Kir6.2 only when both N- and C-termini were replaced. We therefore concluded that nucleotide-dependent gating was regulated by the N- and C-terminal domains irrespective of the transmembrane domains.
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PMID:Cytoplasmic terminus domains of Kir6.x confer different nucleotide-dependent gating on the ATP-sensitive K+ channel. 976 30