title: Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor.
abstract: Humanin is a secreted bioactive peptide that is protective in a variety of death models, including cell-based neuronal death models related to Alzheimer's disease (AD). To mediate the protective effect in AD-related death models, Humanin signals via a cell-surface receptor that is generally composed of three subunits: ciliary neurotrophic factor receptor α, WSX-1 and gp130 (heterotrimeric Humanin receptor; htHNR). However, the protective effect of Humanin via the htHNR is weak (EC50=1-10 μM); therefore, it is possible that another physiological agonist for this receptor exists in vivo. In the current study, calmodulin-like skin protein (CLSP), a calmodulin relative with an undefined function, was shown to be secreted and inhibit neuronal death via the htHNR with an EC50 of 10-100 pM. CLSP was highly expressed in the skin, and the concentration in circulating normal human blood was ~5 nM. When administered intraperitoneally in mice, recombinant CLSP was transported across the blood-cerebrospinal fluid (CSF)-barrier and its concentration in the CSF reaches 1/100 of its serum concentration at 1 h after injection. These findings suggest that CLSP is a physiological htHNR agonist.
authors.affiliation: Department of Pharmacology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: M
authors.initials: M
authors.lastname: Nawa
authors.forename: M
authors.initials: M
authors.lastname: Kurita
authors.forename: M
authors.initials: M
authors.lastname: Tokizawa
authors.forename: A
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: M
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D021122:Protein Subunits / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012867:Skin / Q000378:metabolism
chemical_list: C525513:CLSP protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D021122:Protein Subunits; D011506:Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C427211:humanin