A biologic function for an ''orphan'' messenger: D-myo-inositol 3,4,5,6-tetrakisphosphate selectively blocks epithelial calcium-activated chloride channels

被引:84
作者
Ismailov, II
Fuller, CM
Berdiev, BK
Shlyonsky, VG
Benos, DJ
Barrett, KE
机构
[1] UNIV CALIF SAN DIEGO,MED CTR,SCH MED,DEPT MED,SAN DIEGO,CA 92103
[2] UNIV ALABAMA,DEPT PHYSIOL & BIOPHYS,BIRMINGHAM,AL 35294
关键词
signal transduction; chloride transport; inositol phosphates; cystic fibrosis;
D O I
10.1073/pnas.93.19.10505
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Inositol phosphates are a family of water-soluble intracellular signaling molecules derived from membrane inositol phospholipids, They undergo a variety of complex interconversion pathways, and their levels are dynamically regulated within the cytosol in response to a variety of agonists, Relatively little is known about the biological function of most members of this family, with the exception of inositol 1,4,5-trisphosphate. Specifically, the biological functions of inositol tetrakisphosphates are Largely obscure. In this paper, we report that D-myo-inositol 3,4,5,6-tetrakisphosphate (D-Ins(3,4,5,6)P-4) has a direct biphasic (activation/inhibition) effect on an epithelial Ca2+-activated chloride channel. The effect of D-Ins(3,4,5,6)P-4 is not mimicked by other inositol tetrakisphosphate isomers, is dependent on the prevailing calcium concentration, and is influenced when channels are phosphorylated by calmodulin kinase II. The predominant effect of D-Ins(3,4,5,6)P-4 on phosphorylated channels is inhibitory at levels of intracellular calcium observed in stimulated cells, Our findings indicate the biological function of a molecule hitherto considered as an ''orphan'' messenger, They suggest that the molecular target for D-Ins(3,4,5,6)P-4 is a plasma membrane Ca2+-activated chloride channel. Regulation of this channel by D-Ins(3,4,5,6)P-4 and Ca2+ may have therapeutic implications for the disease states of both diabetic nephropathy and cystic fibrosis.
引用
收藏
页码:10505 / 10509
页数:5
相关论文
共 16 条
  • [1] BARRETT KE, 1993, AM J PHYSIOL, V265, pC859
  • [2] CALCIUM SIGNALING
    CLAPHAM, DE
    [J]. CELL, 1995, 80 (02) : 259 - 268
  • [3] CLARKE LL, 1993, PHARM RESP TRACT, P505
  • [4] Cloning of an epithelial chloride channel from bovine trachea
    Cunningham, SA
    Awayda, MS
    Bubien, JK
    Ismailov, II
    Arrate, MP
    Berdiev, BK
    Benos, DJ
    Fuller, CM
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (52) : 31016 - 31026
  • [5] FONG P, 1995, J MEMBRANE BIOL, V144, P189
  • [6] CFTR
    FULLER, CM
    BENOS, DJ
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1992, 263 (02): : C267 - C286
  • [7] FULLER CM, 1994, J BIOL CHEM, V269, P26642
  • [8] ISMAILOV II, 1994, J BIOL CHEM, V269, P10235
  • [9] ELEVATION OF INOSITOL TETRAKISPHOSPHATE PARALLELS INHIBITION OF CA2+-DEPENDENT CL- SECRETION IN T84 CELLS
    KACHINTORN, U
    VAJANAPHANICH, M
    BARRETT, KE
    TRAYNORKAPLAN, AE
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1993, 264 (03): : C671 - C676
  • [10] CARBACHOL STIMULATES CL- SECRETION VIA ACTIVATION OF 2 DISTINCT APICAL CL- PATHWAYS IN CULTURED HUMAN T-84 INTESTINAL EPITHELIAL MONOLAYERS
    MCEWAN, GTA
    HIRST, BH
    SIMMONS, NL
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1994, 1220 (03): : 241 - 247