Lynx1 prototoxins: critical accessory proteins of neuronal nicotinic acetylcholine receptors

Abstract

Nicotinic receptors of the cholinergic system are ligand-gated ion channels, responding to the excitatory neurotransmitter, acetylcholine, and the addictive component of tobacco, nicotine. They help to transduce salient information in the environment by activating specific neural circuitry in normal and disease states. While nicotinic receptors are promising neurological and neuropsychiatric disorder targets, they have fallen out of favor after several late-stage clinical failures. Targeting the complex of the nicotinic receptor, including lynx1 accessory proteins, could be the key to unlocking the intractable nAChR for therapeutic development. Lynx1 binds to the extracellular face of the nAChR and acts as a critical modulator, suppressing memory, learning, and plasticity. Lynx1 removal in animal models leads to memory and plasticity enhancements, some of which have therapeutic relevance for neuropsychiatric and neurological disease. A review of the lynx1 accessory modulator and its role in modulating neuronal nAChRs will be discussed.

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

“…Lynx2 may also intracellularly suppress expression of lower affinity α4β2 receptors ( 39 ) indirectly promoting the preferential expression of α5 containing high affinity nicotinic receptors in Chrna5+ neurons. However, other lynxes such as Lynx1 which negatively modulates α4β2 receptors ( 41 ) were expressed at similar levels in the majority of cells across all three groups. The distinct pattern of expression of specific lynxes in Chrna5+ neurons suggests unexpectedly complex endogenous control of nicotinic responses in these prefrontal subplate neurons.…”

“…Lynx2 may also intracellularly suppress expression of lower affinity α4β2 receptors (39) indirectly promoting the preferential expression of α5 containing high affinity nicotinic receptors in Chrna5+ neurons. However, other lynxes such as Lynx1 which negatively modulates α4β2 receptors (41) were expressed at similar levels in the majority of cells across all three groups.…”

“…Lynx1) are expressed. To cleave GPI-anchored proteins, we used the PLC activator compound m-3M3FBS (47,(62)(63)(64) the direction of these effects may be difficult to predict, however, since soluble and endogenous GPI-anchored prototoxins have different effects on nicotinic receptors (41). Since previous work predicts a substantial modulatory role for endogenous Ly6g6e, we obtained purified water-soluble recombinant Ly6g6e protein and examined its effects on optogenetic nicotinic responses in labeled Chrna5+ and Syt6+ neurons (Fig 4F).…”

α9-Containing Nicotinic Receptors in Cancer

“…The proteins that stably associate with nAChRs comprise the LY6 prototoxin family, a family of small modulatory proteins that can interact with numerous targets. These proteins have a three-dimensional structure that is similar to that found in snake venom neurotoxins (Miwa, 2021). Some of them are secreted as water-soluble proteins, and others are bound to cell membranes by a glycosylphosphatidylinositol (GPI) anchor.…”

Differential Expression Patterns of Lynx Proteins and Involvement of Lynx1 in Prepulse Inhibition

“…In addition to their actions on membrane-bound nAChRs, lynx proteins may also affect the trafficking of nAChR subunits to the membrane via association in the endoplasmic reticulum ( Nichols et al, 2014 ; Miwa et al, 2019 ). The ability of lynx proteins to modulate these cholinergic processes through both extracellular and intracellular mechanisms has important implications for cognitive aspects of neurological and psychiatric diseases ( Smith et al, 2018 ; Artoni et al, 2020 ; Miwa, 2020 ). Indeed, prior studies in mice lacking the lynx1 (lynx1 –/– ) and lynx2 (lynx2 –/– ) proteins have provided foundational insights into the function of these endogenous modulators.…”