TY  - JOUR
AU  - Haenisch, Britta
AU  - Huber, Michael
AU  - Wilhelm, Thomas
AU  - Steffens, Michael
AU  - Molderings, Gerhard J
TI  - Investigation into mechanisms mediating the inhibitory effect of 1,4-benzodiazepines on mast cells by gene expression profiling.
JO  - Life sciences
VL  - 92
IS  - 6-7
SN  - 0024-3205
CY  - New York, NY [u.a.]
PB  - Elsevier Science
M1  - DZNE-2020-03148
SP  - 345-351
PY  - 2013
AB  - This study aims to identify by a molecular genetic approach potential targets in mast cells at which 1,4-benzodiazepines may cause their inhibitory effect on mast cell activity.Gene expression analyses with microarray gene chip and/or quantitative PCR were performed using 1,4-benzodiazepine-treated human mast cell leukemia HMC-1.2 cells, promyelocytic leukemia HL-60 cells and human mast cells from healthy volunteers and patients with mast cell activation disease (MCAD). Pathway analysis was applied to search for enriched biological functions and canonical pathways within differentially regulated genes.Both neoplastic and normal human mast cells express several GABA(A) receptor subunits at the mRNA level. In mast cells from MCAD patients expression of some GABA(A) receptor subunits and expression of the translocator protein TSPO are increased compared with those from healthy controls. Expression of the protein tyrosine kinases Lyn, Fgr and Yes1 was increased in HMC-1.2 cells as compared with the ontogenetically related HL60 cells. Differences in gene regulation in HMC-1.2 cells after treatment with the 1,4-benzodiazepines clonazepam, flunitrazepam and 4-chlorodiazepam suggested that signaling and gene expression induced by clonazepam was similar to that of flunitrazepam but different from that of 4-chlorodiazepam. This conclusion is supported by the results of the pathway analysis.A novel type of GABA(A) receptors on mast cells appears to be involved in the inhibition of mast cell activity by 1,4-benzodiazepines. These receptors seem to be composed without γ subunits suggesting unique pharmacological properties. An action at Src-kinases, or at TSPO located in the plasma membrane may also be involved.
KW  - Adult
KW  - Aged
KW  - Benzodiazepinones: pharmacology
KW  - Clonazepam: pharmacology
KW  - Female
KW  - Flunitrazepam: pharmacology
KW  - Gene Expression: drug effects
KW  - Gene Expression Profiling: methods
KW  - HL-60 Cells
KW  - Humans
KW  - Male
KW  - Mast Cells: drug effects
KW  - Mastocytosis: genetics
KW  - Microarray Analysis: methods
KW  - Middle Aged
KW  - Polymerase Chain Reaction: methods
KW  - Benzodiazepinones (NLM Chemicals)
KW  - 4'-chlorodiazepam (NLM Chemicals)
KW  - Clonazepam (NLM Chemicals)
KW  - Flunitrazepam (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23352970
DO  - DOI:10.1016/j.lfs.2013.01.010
UR  - https://pub.dzne.de/record/136826
ER  -