Are nicotinic acetylcholine receptors coupled to G proteins?

Abstract

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand-gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

“…The concept of a7 as a dual metabotropic/ionotropic receptor is attracting increasing attention (Kabbani et al, 2013). a7 binds both Ga and Gbg proteins through the M3-M4 loop and enables a downstream calcium signaling response that can persist beyond the expected time course of channel activation (Fig.…”

“…a7 binds both Ga and Gbg proteins through the M3-M4 loop and enables a downstream calcium signaling response that can persist beyond the expected time course of channel activation (Fig. 5) (Kabbani et al, 2013;King et al, 2015). Moreover, in lymphocyte T cells, mobilization of Ca 21 through the a7 channel is not necessarily required for the nicotine-induced release of Ca 21 from the internal stores (Razani-Boroujerdi et al, 2007).…”

“…Moreover, in lymphocyte T cells, mobilization of Ca 21 through the a7 channel is not necessarily required for the nicotine-induced release of Ca 21 from the internal stores (Razani-Boroujerdi et al, 2007). Channel-independent signal transduction has been related to the role of a7 in inflammation (de Jonge and Ulloa, 2007;Thomsen and Mikkelsen, 2012) and in neurite growth (Nordman and Kabbani, 2012;Kabbani et al, 2013).…”

“…The transient increase of calcium may also lead to a sustained calcium response by a calcium-induced calcium release (CICR) mechanism through IP 3 receptors. As a metabotropic receptor, a7 mediates intracellular signals by binding to Ga and Gbg proteins and several other partners (Kabbani et al, 2013;King et al, 2015). In immune cells, a7 has been shown to be involved in several intracellular pathways; although not yet fully deciphered mechanistically, these pathways lead to potent anti-inflammatory effects.…”

“…The long intracellular region (ICD) between TM3 and TM4 is highly variable and particularly short in prokaryotic pLGICs. It is thought to be associated with cytoskeletal proteins and involved in channel modulation in all pLGICs (Kabbani et al, 2013). As shown in the figure, in a7, this region contains determinants of channel conductance (Andersen et al, , 2013 and mediates several intracellular signals (Paulo et al, 2009;Jones et al, 2010).…”