Antagonism by 8-hydroxy-2(di-n-propylamino)tetraline and other serotonin agonists of muscarinic M1-type receptors coupled to inositol phospholipid breakdown in human IMR-32 and SK-N-MC neuroblastoma cells.
IMR-32 and SK-N-MC cells were found to contain [3H]quinuclidinyl benzilate specific binding sites inhibited by pirenzepine in a manner suggesting the presence of both M1-type and M2-type muscarinic receptor recognition sites. Neither cell had detectable [3H]8-OH-DPAT binding sites. Carbachol stimulated the rate of inositol phospholipid breakdown in IMR-32 and SK-N-MC human neuroblastoma cells with an EC50 value of about 50 microM in both cases. Pirenzepine inhibited the carbachol (100 microM)-stimulated inositol phospholipid breakdown in both cells with Hill slopes of unity and IC50 values of 15 nM (IMR-32) and 12 nM (SK-N-MC). The 5-HT1A receptor agonist 8-OH-DPAT competitively inhibited carbachol-stimulated inositol phospholipid breakdown with pA2 values of 5.78 (IMR-32) and 5.61 (SK-N-MC). These values are consistent with the inhibitory potency of 8-OH-DPAT towards [3H]quinuclidinyl benzilate binding in these cells. The 5-HT agonists 5-MeODMT and buspirone at micromolar concentrations inhibited carbachol-stimulated breakdown in IMR-32 cells. The inhibition by 8-OH-DPAT and 5-MeODMT was not affected by preincubation with (-)alprenolol. 5-HT (10-100 microM) was without effect on either basal or carbachol-stimulated breakdown. It is concluded that IMR-32 and SK-N-MC neuroblastoma cells express muscarinic M1-type but not serotoninergic receptors coupled to phosphoinositide-specific phospholipase C. 8-OH-DPAT acts as a weak antagonist at these muscarinic receptors.
Fowler
C J
CJ
CNS1 Research and Development, Astra Research Centre, Södertälje, Sweden.
Ahlgren
P C
PC
O'Neill
C
C
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002065:Buspirone / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008732:Methoxydimethyltryptamines / Q000494:pharmacology; D018727:Muscarinic Antagonists; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010716:Phosphatidylinositols / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000378:metabolism / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*; D014316:Tritium; D014407:Tumor Cells, Cultured
D007295:Inositol Phosphates; D008732:Methoxydimethyltryptamines; D018727:Muscarinic Antagonists; D010716:Phosphatidylinositols; D010743:Phospholipids; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D014316:Tritium; D011813:Quinuclidinyl Benzilate; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002217:Carbachol; D002065:Buspirone