Characteristics and consequences of muscarinic receptor activation by tau protein.
It was recently suggested that tau protein released as a result of neuronal death is toxic to neighbouring cells, an effect that is mediated through the activation of muscarinic M1 and/or M3 receptors. Nevertheless, why tau protein and not other native muscarinic agonists, like ACh, can induce this neurotoxicity remains unknown. To clarify this issue, we analysed the different responses and properties of muscarinic receptors in response to stimulation by tau or ACh. The results revealed that the tau protein has an affinity for muscarinic receptors of around one order of magnitude higher than that of ACh. Furthermore, while the repeated stimulation with ACh induces desensitization of the muscarinic receptors, reiterate stimulation with tau failed to produce this phenomenon. Finally, we found the tau protein to be very stable in the extracellular milieu. These studies provide valuable information to help understand tau toxicity on neural cells bearing M1 or M3 muscarinic receptors and its contribution to neurodegenerative progression in tauopathies.
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049 Madrid, Spain.
Alberto
A
Gómez-Ramos
Miguel
M
Díaz-Hernández
Alicia
A
Rubio
Juan Ignacio
JI
Díaz-Hernández
Maria Teresa
MT
Miras-Portugal
Jesus
J
Avila
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002522:Chlorocebus aethiops; D004361:Drug Tolerance; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D043643:Receptor, Muscarinic M1 / Q000819:agonists*; D043587:Receptor, Muscarinic M3 / Q000819:agonists*; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*
D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D016875:tau Proteins; D000109:Acetylcholine; D002118:Calcium