Alpha 7 nicotinic receptor coupling to heterotrimeric G proteins modulates RhoA activation, cytoskeletal motility, and structural growth

Abstract

Nicotinic acetylcholine receptors (nAChRs) modulate the growth and structure of neurons throughout the nervous system. Ligand stimulation of the a7 nAChR has been shown to regulate the large heterotrimeric GTP-binding protein (G protein) signaling in various types of cells. Here, we demonstrate a role for a7 nAChR/G protein interaction in the activation of the small (monomeric) RhoA GTPase leading to cytoskeletal changes during neurite growth. Treatment of PC12 cells with the a7 nAChR agonist choline or PNU-282987 was associated with an increase in RhoA activity and an inhibition in neurite growth. Specifically, choline treatment was found to attenuate the velocity of microtubule growth at the growth cone and decrease the rate of actin polymerization throughout the cell. The effects of a7 nAChR activation were abolished by expression of a dominant negative a7 nAChR (a7 345-348A ) deficient in G protein coupling. Proteomic analysis of immunoprecipitated a7 nAChR complexes from differentiating PC12 cells and synaptic fractions of the developing mouse hippocampus revealed the existence of Rho GTPase-regulating guanine nucleotide exchange factors within a7 nAChR interactomes. These findings underscore the role of a7 nAChR/G protein in cytoskeletal regulation during neurite growth.

Canonical and Novel Non-Canonical Cholinergic Agonists Inhibit ATP-Induced Release of Monocytic Interleukin-1β via Different Combinations of Nicotinic Acetylcholine Receptor Subunits α7, α9 and α10

“…There is increasing evidence, that signaling via nAChR subunit α7 induces Ca 2+ signals and that signaling-related proteins including G proteins can interact with a cytoplasmic loop of this subunit (Kabbani et al, 2013; King and Kabbani, 2016; Valbuena and Lerma, 2016). Similar protein-protein interactions might also occur for subunit α9.…”

The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice

“…Although there has been mounting evidence that α7 nAChRs have a large intracellular (Paulo et al, 2009) interactome that may function both as metabotropic as well as ionotropic receptors (de Jonge and Ulloa, 2007; Kabbani et al, 2013; King and Kabbani, 2016), specific signaling intermediaries remain to be identified. The conformational changes induced by the binding of orthosteric ligands may modulate the Jak/Stat cascade, which is implicated in the regulation of inflammation (de Jonge et al, 2005).…”

Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells

“…␣7 nAChR has been shown to modulate several signaling pathways, such as JAK2/STAT3/NF-B, PLC/ inositol 1,4,5-trisphosphate, and PI3K/Akt/Nrf-2 pathways, which in immune cells result in potent anti-inflammatory effects through inflammatory cytokine production inhibition and overexpression of hemooxigenase-1 (54,(57)(58)(59). Also, a direct coupling of ␣7 nAChR to G-protein has been recently described (60,61). Thus, our study opens doors to decipher in human NK cells the highly complex signaling pathways triggered by ␣7 nAChR and their association to different cell functions.…”