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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Cereb+Blood+Flow+Metab
2016 ; 36
(11
): 1913-1928
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P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain
endothelium during inflammatory pain
#MMPMID27466374
Tome ME
; Herndon JM
; Schaefer CP
; Jacobs LM
; Zhang Y
; Jarvis CK
; Davis TP
J Cereb Blood Flow Metab
2016[Nov]; 36
(11
): 1913-1928
PMID27466374
show ga
P-glycoprotein (PgP), a drug efflux pump in blood-brain barrier endothelial
cells, is a major clinical obstacle for effective central nervous system drug
delivery. Identifying PgP regulatory pathways that can be exploited clinically is
critical for improving central nervous system drug delivery. We previously found
that PgP activity increases in rat brain microvessels concomitant with decreased
central nervous system drug delivery in response to acute peripheral inflammatory
pain. In the current study, we tested the hypothesis that PgP traffics to the
luminal plasma membrane of the microvessel endothelial cells from intracellular
stores during peripheral inflammatory pain. Using immunofluorescence microscopy,
we detected PgP in endothelial cell nuclei and in the luminal plasma membrane in
control animals. Following peripheral inflammatory pain, luminal PgP staining
increased while staining in the nucleus decreased. Biochemical analysis of
nuclear PgP content confirmed our visual observations. Peripheral inflammatory
pain also increased endothelial cell luminal staining of polymerase 1 and
transcript release factor/cavin1 and serum deprivation response protein/cavin2,
two caveolar scaffold proteins, without changing caveolin1 or protein kinase C
delta binding protein/cavin3 location. Our data (a) indicate that PgP traffics
from stores in the nucleus to the endothelial cell luminal membrane in response
to peripheral inflammatory pain; (b) provide an explanation for our previous
observation that peripheral inflammatory pain inhibits central nervous system
drug uptake; and (c) suggest a novel regulatory mechanism for PgP activity in rat
brain.
|ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism
[MESH]