PMID- 10075733
OWN - NLM
STAT- MEDLINE
DCOM- 19990415
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 12
DP  - 1999 Mar 19
TI  - Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the
      photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt
      disease.
PG  - 8269-81
AB  - Many substrates for P-glycoprotein, an ABC transporter that mediates multidrug
      resistance in mammalian cells, have been shown to stimulate its ATPase activity
      in vitro. In the present study, we used this property as a criterion to search
      for natural and artificial substrates and/or allosteric regulators of ABCR, the
      rod photoreceptor-specific ABC transporter responsible for Stargardt disease, an 
      early onset macular degeneration. ABCR was immunoaffinity purified to apparent
      homogeneity from bovine rod outer segments and reconstituted into liposomes.
      All-trans-retinal, a candidate ligand, stimulates the ATPase activity of ABCR
      3-4-fold, with a half-maximal effect at 10-15 microM. 11-cis- and 13-cis-retinal 
      show similar activity. All-trans-retinal stimulates the ATPase activity of ABCR
      with Michaelis-Menten behavior indicative of simple noncooperative binding that
      is associated with a rate-limiting enzyme-substrate intermediate in the pathway
      of ATP hydrolysis. Among 37 structurally diverse non-retinoid compounds,
      including nine previously characterized substrates or sensitizers of
      P-glycoprotein, only four show significant ATPase stimulation when tested at 20
      microM. The dose-response curves of these four compounds are indicative of
      multiple binding sites and/or modes of interaction with ABCR. Two of these
      compounds, amiodarone and digitonin, can act synergistically with
      all-trans-retinal, implying that they interact with a site or sites on ABCR
      different from the one with which all-trans-retinal interacts. Unlike retinal,
      amiodarone appears to interact with both free and ATP-bound ABCR. Together with
      clinical observations on Stargardt disease and the localization of ABCR to rod
      outer segment disc membranes, these data suggest that retinoids, and most likely 
      retinal, are the natural substrates for transport by ABCR in rod outer segments. 
      These observations have significant implications for understanding the visual
      cycle and the pathogenesis of Stargardt disease and for the identification of
      compounds that could modify the natural history of Stargardt disease or other
      retinopathies associated with impaired ABCR function.
FAU - Sun, H
AU  - Sun H
AD  - Department of Molecular Biology and Genetics, The Johns Hopkins University School
      of Medicine, Baltimore, Maryland 21205, USA.
FAU - Molday, R S
AU  - Molday RS
FAU - Nathans, J
AU  - Nathans J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Norisoprenoids)
RN  - 0 (Terpenes)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - A7NRR1HLH6 (beta-ionone)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - KOO5CM684H (Digitonin)
RN  - N3RQ532IUT (Amiodarone)
RN  - RR725D715M (Retinaldehyde)
SB  - IM
MH  - ATP-Binding Cassette Transporters/isolation & purification/*metabolism
MH  - Adenosine Triphosphatases/metabolism
MH  - Adenosine Triphosphate/*metabolism
MH  - Amiodarone/administration & dosage/pharmacology
MH  - Animals
MH  - Carbohydrate Sequence
MH  - Cattle
MH  - Digitonin/administration & dosage/pharmacology
MH  - Hydrolysis
MH  - In Vitro Techniques
MH  - Kinetics
MH  - Macular Degeneration/*metabolism
MH  - Models, Chemical
MH  - Molecular Sequence Data
MH  - Molecular Weight
MH  - *Norisoprenoids
MH  - Retinaldehyde/*pharmacology
MH  - Rod Cell Outer Segment/drug effects/*metabolism
MH  - Terpenes/administration & dosage/pharmacology
EDAT- 1999/03/13 00:00
MHDA- 1999/03/13 00:01
CRDT- 1999/03/13 00:00
PHST- 1999/03/13 00:00 [pubmed]
PHST- 1999/03/13 00:01 [medline]
PHST- 1999/03/13 00:00 [entrez]
AID - 10.1074/jbc.274.12.8269 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 19;274(12):8269-81. doi: 10.1074/jbc.274.12.8269.