Thyroid hormones reduce nicotinic receptor mediated currents in SH-SY5Y neuroblastoma cells.

BACKGROUND: Thyroid hormones (THs) are crucial for maturation and functioning of mammalian CNS. THs "classical" signaling involves nuclear receptors binding but also their non genomic actions, as rapid modulators of cell activity, are widely recognized. Since THs imbalance affects cognition and the cholinergic system is deeply involved in learning and memory processes we have studied THs effects at the level of the nicotinic acetylcholine receptors (nAchR). METHODS: We used the patch-clamp technique to analyze T3 and T4 modulation of nicotine (NIC)-mediated current in SH-SY5Y neuroblastoma cells. RESULTS: Both hormones decreased NIC-evoked current in a dose dependent fashion. The antagonism was reversible, not competitive and not blocked by Tetrac, an integrin αVß3 receptor antagonist. A similar effect was detected with the endogenous agonist Acetylcholine. THs potencies were higher at 100 µM NIC (IC50 = 4.6 ± 2 µM for T3 and 4.8 ± 2 µM for T4) compared to those measured at 10 µM NIC (IC50 = 10 ± 4 µM for T3 and 8 ± 4 µM for T4). Furthermore, the efficacy of THs reached almost 90% at 100 µM NIC while was about 30 % at 10 µM NIC. THs inhibited nAchR-mediated currents by enhancing receptor desensitization and this effect was more pronounced at high agonist concentrations. CONCLUSIONS: Our results make light on a new non genomic activity of THs at the level of nAchR. This mechanism of action  of THs  can provide  a new explanation for the cognitive deficits associated with tyroid dysfunction.

Positive allosteric modulators of α7 nicotinic acetylcholine receptors affect neither the function of other ligand- and voltage-gated ion channels and acetylcholinesterase, nor ß-amyloid content.

The activity of positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (AChRs), including 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), 3-furan-2-yl-N-o-tolylacrylamide (PAM-3), and 3-furan-2-yl-N-phenylacrylamide (PAM-4), was tested on a variety of ligand- [i.e., human (h) α7, rat (r) α9α10, hα3-containing AChRs, mouse (m) 5-HT3AR, and several glutamate receptors (GluRs)] and voltage-gated (i.e., sodium and potassium) ion channels, as well as on acetylcholinesterase (AChE) and ß-amyloid (Aß) content. The functional results indicate that PAM-2 inhibits hα3-containing AChRs (IC50=26±6µM) with higher potency than that for NR1aNR2B and NR1aNR2A, two NMDA-sensitive GluRs. PAM-2 affects neither the activity of m5-HT3ARs, GluR5/KA2 (a kainate-sensitive GluR), nor AChE, and PAM-4 does not affect agonist-activated rα9α10 AChRs. Relevant clinical concentrations of PAM-2-4 do not inhibit Nav1.2 and Kv3.1 ion channels. These PAMs slightly enhance the activity of GluR1 and GluR2, two AMPA-sensitive GluRs. PAM-2 does not change the levels of Aß42 in an Alzheimer's disease mouse model (i.e., 5XFAD). The molecular docking and dynamics results using the hα7 model suggest that the active sites for PAM-2 include the intrasubunit (i.e., PNU-120596 locus) and intersubunit sites. These results support our previous study showing that these PAMs are selective for the α7 AChR, and clarify that the procognitive/promnesic/antidepressant activity of PAM-2 is not mediated by other targets.