Modulation of type-1 Ins(1,4,5)P3 receptor channels by the FK506-binding protein, FKBP12.
FK506-binding protein (FKBP12) is highly expressed in neuronal tissue, where it is proposed to localize calcineurin to intracellular calcium-release channels, ryanodine receptors and Ins(1,4,5)P(3) receptors (InsP(3)Rs). The effects of FKBP12 on ryanodine receptors have been well characterized but the nature and function of binding of FKBP12 to InsP(3)R is more controversial, with evidence for and against a tight interaction between these two proteins. To investigate this, we incorporated purified type-1 InsP(3)R from rat cerebellum into planar lipid bilayers to monitor the effects of exogenous recombinant FKBP12 on single-channel activity, using K(+) as the current carrier. Here we report for the first time that FKBP12 causes a substantial change in single-channel properties of the type-1 InsP(3)R, specifically to increase the amount of time the channel spends in a fully open state. In the presence of ATP, FKBP12 can also induce co-ordinated gating with neighbouring receptors. The effects of FKBP12 were reversed by FK506. We also present data showing that rapamycin, at sub-optimal concentrations of Ins(2,4,5)P(3), decreases the rate of calcium release from cerebellar microsomes. These results provide evidence for a direct functional interaction between FKBP12 and the type-1 InsP(3)R.
Dargan
Sheila L
SL
School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.
Lea
Edward J A
EJ
Dawson
Alan P
AP
D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D008081:Liposomes; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D022061:Tacrolimus Binding Protein 1A / Q000502:physiology*
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008081:Liposomes; D018160:Receptors, Cytoplasmic and Nuclear; D022061:Tacrolimus Binding Protein 1A