The Prototoxin lynx1 Acts on Nicotinic Acetylcholine Receptors to Balance Neuronal Activity and Survival In Vivo

Abstract

Nicotinic acetylcholine receptors (nAChRs) affect a wide array of biological processes, including learning and memory, attention, and addiction. lynx1, the founding member of a family of mammalian prototoxins, modulates nAChR function in vitro by altering agonist sensitivity and desensitization kinetics. Here we demonstrate, through the generation of lynx1 null mutant mice, that lynx1 modulates nAChR signaling in vivo. Its loss decreases the EC(50) for nicotine by approximately 10-fold, decreases receptor desensitization, elevates intracellular calcium levels in response to nicotine, and enhances synaptic efficacy. lynx1 null mutant mice exhibit enhanced performance in specific tests of learning and memory. Consistent with reports that mutations resulting in hyperactivation of nAChRs can lead to neurodegeneration, aging lynx1 null mutant mice exhibit a vacuolating degeneration that is exacerbated by nicotine and ameliorated by null mutations in nAChRs. We conclude that lynx1 functions as an allosteric modulator of nAChR function in vivo, balancing neuronal activity and survival in the CNS.

NKCC1-Dependent GABAergic Excitation Drives Synaptic Network Maturation during Early Hippocampal Development

“…S12, available at www.jneurosci.org as supplemental material). Lynx1 is a membrane-anchored protein that interacts with nicotinic acetylcholine receptors (nAChRs) and thereby influences neuronal excitability (Ibañez-Tallon et al, 2002;Miwa et al, 2006). Lynx1 was downregulated both at the mRNA (P1, P5, P15) (Fig.…”

“…Lynx1, a membrane-tethered protein, reduces the agonist sensitivity of nicotinic acetylcholine receptors and accelerates their desensitization, thereby decreasing neuronal excitation (Ibañez-Tallon et al, 2002;Miwa et al, 2006). A downregulation of lynx1 should increase neuronal excitability, thereby partially compensating for the diminished GABAergic excitation in Nkcc1 Ϫ/Ϫ mice.…”

Identification of downstream targets of the Bone Morphogenetic Protein pathway in the Drosophila nervous system

“…CG9335 encodes a putative secreted peptide of 166 amino acids of the Ly-6 superfamily of GPIanchored molecules that have been described in several systems, including Drosophila. Members of this family act as modulators of the nAChR (Miwa et al, 2006), septate junction proteins (Hijazi et al, 2009), and regulate traffic of ion channels (Wu et al, 2010).…”

Water-soluble LYNX1 Residues Important for Interaction with Muscle-type and/or Neuronal Nicotinic Receptors

“…The principal difference of LYNX1 from snake neurotoxins is the presence at its C terminus of a glycosylphosphatidylinositol anchor by which it is attached to the membrane in the vicinity of neuronal nicotinic acetylcholine receptors (nAChRs), 3 thus modulating their functioning (4). In the past decade, the involvement of LYNX1, LYNX2, and other relevant Ly6 members was demonstrated in regulation of behavior (5,6), retinal plasticity (7), and some other processes, including lung cancer cell growth (8 -10).…”