Agonist-induced desensitization and loss of high-affinity binding sites of stably expressed human 5-HT1A receptors.
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Harrington MA, Shaw K, Zhong P, Ciaranello RD
Agonist-induced desensitization and loss of high-affinity binding sites of stably expressed human 5-HT1A receptors.
J Pharmacol Exp Ther. 1994 Mar;268(3):1098-106.
- PubMed ID
- 8138923 [ View in PubMed]
- Abstract
Exposure of HeLa cells stably expressing cloned human 5-hydroxytryptamine (5-HT)1A receptors (HA7 cells) to the agonist 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT) results in a loss of high-affinity binding sites and a desensitization of receptor-adenylate cyclase coupling, as measured by 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase activity. These responses can also be observed after exposure to forskolin, which activates cyclic AMP-dependent protein kinase A or after treatment with known activators of protein kinase C (PKC) such as phorbol-12-myristate 13-acetate (PMA). The responses elicited by exposure to 8-OH-DPAT or PMA can be blocked completely by inhibitors of PKC and also by 24-hr exposure to PMA. Preincubation of HA7 cells with 8-OH-DPAT also stimulates hydrolysis of inositol phospholipids and the production of arachidonic acid. Inhibition of phospholipase A2 with quinacrine or by removal of extracellular Ca++ blocks the agonist-mediated loss of 5-HT1A receptor binding sites. These data demonstrate that agonist-induced down regulation of the 5-HT1A receptor occurs after stimulation of both the PKC and phospholipase A2 signaling pathways, both of which may activate PKC. The subsequent response is a loss of high-affinity ligand binding sites and functional receptor coupling to adenylate cyclase.