Date of Award
neurotoxins, Ly6 genes, Lynx 1, nicotinic acetylcholine receptors
Endogenous short peptide modulators of ion channels provide a new level of regulation of nervous function. Lynx1 was identified as an endogenous mammalian homologue of snake venom peptide neurotoxins capable of binding to and functionally modulating nicotinic cetylcholine receptors (nAChR). Lynx1 is a member of the Ly6-Î±âˆ’neurotoxin superfamily (Ly6SF) of genes. Through extensive database searches, I identified 85 members of this superfamily including previously unidentified vertebrate and invertebrate family members. I show that these proteins are very divergent in their sequences, and identify two conserved subfamilies, snake toxins and immune system expressed Ly6 genes through phylogenetic inference. I also discovered conserved sequences among Ly6SF proteins additional to the cysteines that characterize the three-dimensional topology of Ly6 domain. From these Ly6SF molecules, I characterize three lynx1 homologues: lynx2, lynx3 and Ly6H. These have different and specific expression patterns in the central and peripheral nervous systems. Importantly, like lynx1, lynx2 and lynx3 are able to bind specific nAChR combinations and modulate their desensitization properties, while Ly6H does not bind nor modulate the function of nAChRs. I have also analyzed the in vivo function of lynx2, through the targeted deletion of lynx2 in mice. Lynx2 null mutant (lynx2-/-) mice exhibited increased anxiety, better associative learning and better motor coordination and learning than wild type (WT) mice. Nicotine and nicotinic receptor antagonist, mecamylamine, show distinct effects on motor learning in lynx2-/- mice and WT mice. The properties of this new family of lynx1-like molecules, taken together with those of lynx1 and the secreted Ly6SF member SLURP1 (secreted Ly6/UPAR related protein), suggest a general role for Ly6SF proteins in the modulation of nAChRs and other receptor proteins.
Tekinay, Ayse Begum, "Targeted Disruption of Lynx2 Reveals Distinct Functions for Lynx Homologues in Learning and Behavior" (2007). Student Theses and Dissertations. 28.