Rapid Upregulation of α7 Nicotinic Acetylcholine Receptors by Tyrosine Dephosphorylation

Abstract

␣7 nicotinic acetylcholine receptors (nAChRs) modulate network activity in the CNS. Thus, functional regulation of ␣7 nAChRs could influence the flow of information through various brain nuclei. It is hypothesized here that these receptors are amenable to modulation by tyrosine phosphorylation. In both Xenopus oocytes and rat hippocampal interneurons, brief exposure to a broad-spectrum protein tyrosine kinase inhibitor, genistein, specifically and reversibly potentiated ␣7 nAChR-mediated responses, whereas a protein tyrosine phosphatase inhibitor, pervanadate, caused depression. Potentiation was associated with an increased expression of surface ␣7 subunits and was not accompanied by detectable changes in receptor open probability, implying that the increased function results from an increased number of ␣7 nAChRs. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated exocytosis was shown to be a plausible mechanism for the rapid delivery of additional ␣7 nAChRs to the plasma membrane. Direct phosphorylation/ dephosphorylation of ␣7 subunits was unlikely because mutation of all three cytoplasmic tyrosine residues did not prevent the genisteinmediated facilitation. Overall, these data are consistent with the hypothesis that the number of functional cell surface ␣7 nAChRs is controlled indirectly via processes involving tyrosine phosphorylation.

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

“…17 Thus, we tested the effects of genistein stimulation on differentiated primary human adipocytes. A significant increase of a7nAChR cellular protein content was observed after 3 h treatment with 10 mM genistein (Figure 5b).…”

“…8 Although a wide variety of cellular mechanisms may modulate a7nAChR functional activity, recently tyrosine-kinase de-phosphorylation has been shown to be the major pathway for a rapid upregulating effect on this receptor. 17 Indeed, a broad spectrum of protein tyrosinekinase inhibitors (such as genistein and daidzein) potentiates a7nAChR activity, increasing the number of surface a7nAChR rather than modulating the receptor's open state. 17 The results presented herein suggest that protein tyrosinekinase inhibitors, such as genistein, could be employed for a7nAChR upregulation and for the management of low-grade inflammation linked to human obesity.…”

“…17 Indeed, a broad spectrum of protein tyrosinekinase inhibitors (such as genistein and daidzein) potentiates a7nAChR activity, increasing the number of surface a7nAChR rather than modulating the receptor's open state. 17 The results presented herein suggest that protein tyrosinekinase inhibitors, such as genistein, could be employed for a7nAChR upregulation and for the management of low-grade inflammation linked to human obesity. Further studies are certainly needed in large cohorts of obese patients to establish the therapeutic effects of genistein on a7nAChR activation and on circulating inflammatory cytokine modifications.…”

An Acute Effect of Neuregulin 1β to Suppress α7-Containing Nicotinic Acetylcholine Receptors in Hippocampal Interneurons

“…Most relevant to our experiments are recent observations of rapid exocytosis of ␣7 nAChRs in rat hippocampal interneurons exposed to genistein, a nonspecific protein tyrosine kinase inhibitor (Cho et al, 2005). Genistein enhanced ␣7 currents and pervanadate, a PTP inhibitor, suppressed them.…”

“…The increase in surface ␣7 receptors was associated with a corresponding decrease in intracellular receptors. Cho et al (2005) found that this exchange between intracellular and surface pools was inhibited by botulinum toxin-A, implying a role for soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE), but the trafficking was apparently not dependent on an intact actin network.…”