Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F16%3A00466603" target="_blank" >RIV/67985823:_____/16:00466603 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1038/srep30698" target="_blank" >http://dx.doi.org/10.1038/srep30698</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/srep30698" target="_blank" >10.1038/srep30698</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Popis výsledku v původním jazyce

Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the alpha 3 beta 2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a 'three-finger' fold of SLURP-2 with a conserved beta-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the alpha 3, alpha 4, alpha 5, alpha 7, beta 2, and beta 4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at alpha 4 beta 2 and alpha 3 beta 2-nAChRs (IC50 similar to 0.17 and >3 mu M, respectively) expressed in Xenopus oocytes. In contrast, at alpha 7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 mu M but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with alpha 3 beta 2-nAChRs, while it inhibited cell growth via alpha 7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the 'classical' orthosteric agonist/antagonist binding sites at alpha 7 and alpha 3 beta 2-nAChRs.

Název v anglickém jazyce

Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors

Popis výsledku anglicky

Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the alpha 3 beta 2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a 'three-finger' fold of SLURP-2 with a conserved beta-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the alpha 3, alpha 4, alpha 5, alpha 7, beta 2, and beta 4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at alpha 4 beta 2 and alpha 3 beta 2-nAChRs (IC50 similar to 0.17 and >3 mu M, respectively) expressed in Xenopus oocytes. In contrast, at alpha 7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 mu M but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with alpha 3 beta 2-nAChRs, while it inhibited cell growth via alpha 7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the 'classical' orthosteric agonist/antagonist binding sites at alpha 7 and alpha 3 beta 2-nAChRs.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

ED - Fyziologie

OECD FORD obor

—

Projekt

<a href="/cs/project/GA14-05696S" target="_blank" >GA14-05696S: Hledání mechanismů škodlivého působení amyloidu beta na funkci muskarinových receptorů.</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific Reports

ISSN

2045-2322

e-ISSN

—

Svazek periodika

6

Číslo periodika v rámci svazku

Aug 3

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

17

Strana od-do

—

Kód UT WoS článku

000380664600001

EID výsledku v databázi Scopus

2-s2.0-84981335426