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      The Role of NH 2-terminal Positive Charges in the Activity of Inward Rectifier K ATP Channels

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      Author(s): , ,
      Publication date (Print):
      Journal: The Journal of General Physiology
      Publisher: The Rockefeller University Press
      Keywords: K+ current, KATP, PIP2, Kir6.2, ATP

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          Abstract

          Approximately half of the NH 2 terminus of inward rectifier (Kir) channels can be deleted without significant change in channel function, but activity is lost when more than ∼30 conserved residues before the first membrane spanning domain (M1) are removed. Systematic replacement of the positive charges in the NH 2 terminus of Kir6.2 with alanine reveals several residues that affect channel function when neutralized. Certain mutations (R4A, R5A, R16A, R27A, R39A, K47A, R50A, R54A, K67A) change open probability, whereas an overlapping set of mutants (R16A, R27A, K39A, K47A, R50A, R54A, K67A) change ATP sensitivity. Further analysis of the latter set differentiates mutations that alter ATP sensitivity as a consequence of altered open state stability (R16A, K39A, K67A) from those that may affect ATP binding directly (K47A, R50A, R54A). The data help to define the structural determinants of Kir channel function, and suggest possible structural motifs within the NH 2 terminus, as well as the relationship of the NH 2 terminus with the extended cytoplasmic COOH terminus of the channel.

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          Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor.

          N Inagaki, T Gonoi, J P Clement … (1995)
          A member of the inwardly rectifying potassium channel family was cloned here. The channel, called BIR (Kir6.2), was expressed in large amounts in rat pancreatic islets and glucose-responsive insulin-secreting cell lines. Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) and was inhibited by sulfonylureas and activated by diazoxide. The data indicate that these pancreatic beta cell potassium channels are a complex composed of at least two subunits--BIR, a member of the inward rectifier potassium channel family, and SUR, a member of the ATP-binding cassette superfamily. Gene mapping data show that these two potassium channel subunit genes are clustered on human chromosome 11 at position 11p15.1.
          Article 0 comments Cited 189 times – based on 0 reviews     Review now
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            Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor.

            Chenyan Zhao, Abigail Tucker, F Gribble … (1997)
            ATP-sensitive potassium channels (K-ATP channels) couple cell metabolism to electrical activity and are important in the physiology and pathophysiology of many tissues. In pancreatic beta-cells, K-ATP channels link changes in blood glucose concentration to insulin secretion. They are also the target for clinically important drugs such as sulphonylureas, which stimulate secretion, and the K+ channel opener diazoxide, which inhibits insulin release. Metabolic regulation of K-ATP channels is mediated by changes in intracellular ATP and Mg-ADP levels, which inhibit and activate the channel, respectively. The beta-cell K-ATP channel is a complex of two proteins: an inward-rectifier K+ channel subunit, Kir6.2, and the sulphonylurea receptor, SUR1. We show here that the primary site at which ATP acts to mediate K-ATP channel inhibition is located on Kir6.2, and that SUR1 is required for sensitivity to sulphonylureas and diazoxide and for activation by Mg-ADP.
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              Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2.

              Christina Ball, Donald W. Hilgemann (1996)
              Cardiac Na+,Ca2+ exchange is activated by a mechanism that requires hydrolysis of adenosine triphosphate (ATP) but is not mediated by protein kinases. In giant cardiac membrane patches, ATP acted to generate phosphatidylinositol-4,5-bisphosphate (PIP2) from phosphatidylinositol (PI). The action of ATP was abolished by a PI-specific phospholipase C (PLC) and recovered after addition of exogenous PI; it was reversed by a PIP2-specific PLC; and it was mimicked by exogenous PIP2. High concentrations of free Ca2+ (5 to 20 microM) accelerated reversal of the ATP effect, and PLC activity in myocyte membranes was activated with a similar Ca2+ dependence. Aluminum reversed the ATP effect by binding with high affinity to PIP2. ATP-inhibited potassium channels (KATP) were also sensitive to PIP2, whereas Na+,K+ pumps and Na+ channels were not. Thus, PIP2 may be an important regulator of both ion transporters and channels.
              Article 0 comments Cited 104 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Gen Physiol
                Title: The Journal of General Physiology
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1295
                ISSN (Electronic): 1540-7748
                Publication date (Print): September 2002
                Volume: 120
                Issue: 3
                Pages: 437-446
                Affiliations
                Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110
                Author notes

                Address all correspondence and reprint requests to Colin G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Fax: (314) 362-7463; E-mail: cnichols@ 123456cellbio.wustl.edu

                Article
                Publisher ID: 20028621
                DOI: 10.1085/jgp.20028621
                PMC ID: 2229524
                PubMed ID: 12198096
                SO-VID: 78f2087a-d763-43f9-a976-d8a9406ab998
                Copyright © Copyright © 2002, The Rockefeller University Press
                History
                Date received : 6 May 2002
                Date revision received : 24 July 2002
                Date accepted : 30 July 2002
                Categories
                Subject: Article

                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: pip2,kir6.2,katp,k+ current,atp
                Data availability:
                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: pip2, kir6.2, katp, k+ current, atp

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