Abstract
The cannabinoid 1 receptor (CB1R) is one of the most abundant seven transmembrane (7TM) spanning/G-protein-coupled receptors in the central nervous system and plays an important role in pain transmission, feeding, and the rewarding effects of cannabis. Tolerance to cannabinoids has been widely observed after long-term use, with concomitant receptor desensitization and/or down-regulation depending on the brain region studied. Several CB1R agonists promote receptor internalization after activation, but the postendocytic sorting of the receptor has not been studied in detail. Utilizing human embryonic kidney (HEK293) cells stably expressing the CB1R and primary cultured neurons expressing endogenous CB1R, we show that treatment with cannabinoid agonists results in CB1R degradation after endocytosis and that the G-protein-coupled receptor-associated sorting protein GASP1 plays a major role in the postendocytic sorting process. Thus, these results may identify a molecular mechanism underlying tolerance and receptor down-regulation after long-term use of cannabinoids.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 802-811 |
| Number of pages | 10 |
| Journal | FASEB Journal |
| Volume | 21 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2007 |
| Externally published | Yes |
Fingerprint
Keywords
- Degradation
- GPCR
- Postendocytic sorting
- Tolerance
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
Cite this
Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. / Martini, Lene; Waldhoer, Maria; Pusch, Margareta; Kharazia, Viktor; Fong, Jamie; Lee, Josephine H.; Freissmuth, Clarissa; Whistler, Jennifer.
In: FASEB Journal, Vol. 21, No. 3, 01.03.2007, p. 802-811.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1
AU - Martini, Lene
AU - Waldhoer, Maria
AU - Pusch, Margareta
AU - Kharazia, Viktor
AU - Fong, Jamie
AU - Lee, Josephine H.
AU - Freissmuth, Clarissa
AU - Whistler, Jennifer
PY - 2007/3/1
Y1 - 2007/3/1
N2 - The cannabinoid 1 receptor (CB1R) is one of the most abundant seven transmembrane (7TM) spanning/G-protein-coupled receptors in the central nervous system and plays an important role in pain transmission, feeding, and the rewarding effects of cannabis. Tolerance to cannabinoids has been widely observed after long-term use, with concomitant receptor desensitization and/or down-regulation depending on the brain region studied. Several CB1R agonists promote receptor internalization after activation, but the postendocytic sorting of the receptor has not been studied in detail. Utilizing human embryonic kidney (HEK293) cells stably expressing the CB1R and primary cultured neurons expressing endogenous CB1R, we show that treatment with cannabinoid agonists results in CB1R degradation after endocytosis and that the G-protein-coupled receptor-associated sorting protein GASP1 plays a major role in the postendocytic sorting process. Thus, these results may identify a molecular mechanism underlying tolerance and receptor down-regulation after long-term use of cannabinoids.
AB - The cannabinoid 1 receptor (CB1R) is one of the most abundant seven transmembrane (7TM) spanning/G-protein-coupled receptors in the central nervous system and plays an important role in pain transmission, feeding, and the rewarding effects of cannabis. Tolerance to cannabinoids has been widely observed after long-term use, with concomitant receptor desensitization and/or down-regulation depending on the brain region studied. Several CB1R agonists promote receptor internalization after activation, but the postendocytic sorting of the receptor has not been studied in detail. Utilizing human embryonic kidney (HEK293) cells stably expressing the CB1R and primary cultured neurons expressing endogenous CB1R, we show that treatment with cannabinoid agonists results in CB1R degradation after endocytosis and that the G-protein-coupled receptor-associated sorting protein GASP1 plays a major role in the postendocytic sorting process. Thus, these results may identify a molecular mechanism underlying tolerance and receptor down-regulation after long-term use of cannabinoids.
KW - Degradation
KW - GPCR
KW - Postendocytic sorting
KW - Tolerance
UR - http://www.scopus.com/inward/record.url?scp=33847403181&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33847403181&partnerID=8YFLogxK
U2 - 10.1096/fj.06-7132com
DO - 10.1096/fj.06-7132com
M3 - Article
C2 - 17197383
AN - SCOPUS:33847403181
VL - 21
SP - 802
EP - 811
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 3
ER -