Abstract
The novel neuropeptide spexin (SPX) was discovered to activate galanin receptor 2 (GALR2) and 3 (GALR3) but not galanin receptor 1 (GALR1). Although GALR2 is known to display a function, particularly in anxiety, depression, and appetite regulation, the further determination of its function would benefit from a more stable and selective agonist that acts only at GALR2. In the present study, we developed a GALR2-specific agonist with increased stability in serum. As galanin (GAL) showed a low affinity to GALR3, the residues in SPX were replaced with those in GAL, revealing that particular mutations such as Gln5 → Asn, Met7 → Ala, Lys11 → Phe, and Ala13 → Pro significantly decreased potencies toward GALR3 but not toward GALR2. Quadruple (Qu) mutation of these residues still retained potency to GALR2 but totally abolished the potency to both GALR3 and GALR1. The first amino acid modifications or D-Asn1 substitution significantly increased the stability when they are incubated in 100% fetal bovine serum. Intracerebroventricular administration of the mutant peptide with D-Asn1 and quadruple substitution (dN1-Qu) exhibited an anxiolytic effect in mice. Taken together, the GALR2-specific agonist with increased stability can greatly help delineation of GALR2-mediated functions and be very useful for treatments of anxiety disorder.
| Original language | English |
|---|---|
| Article number | 21453 |
| Journal | Scientific Reports |
| Volume | 6 |
| DOIs | |
| Publication status | Published - 2016 Feb 24 |
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Cite this
Development of spexin-based human galanin receptor type II-specific agonists with increased stability in serum and anxiolytic effect in mice. / Reyes-Alcaraz, Arfaxad; Lee, Yoo Na; Son, Gi Hoon; Kim, Nam Hoon; Kim, Dong Kyu; Yun, Seongsik; Kim, Dong-Hun; Hwang, Jong-Ik; Seong, Jae Young.
In: Scientific Reports, Vol. 6, 21453, 24.02.2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Development of spexin-based human galanin receptor type II-specific agonists with increased stability in serum and anxiolytic effect in mice
AU - Reyes-Alcaraz, Arfaxad
AU - Lee, Yoo Na
AU - Son, Gi Hoon
AU - Kim, Nam Hoon
AU - Kim, Dong Kyu
AU - Yun, Seongsik
AU - Kim, Dong-Hun
AU - Hwang, Jong-Ik
AU - Seong, Jae Young
PY - 2016/2/24
Y1 - 2016/2/24
N2 - The novel neuropeptide spexin (SPX) was discovered to activate galanin receptor 2 (GALR2) and 3 (GALR3) but not galanin receptor 1 (GALR1). Although GALR2 is known to display a function, particularly in anxiety, depression, and appetite regulation, the further determination of its function would benefit from a more stable and selective agonist that acts only at GALR2. In the present study, we developed a GALR2-specific agonist with increased stability in serum. As galanin (GAL) showed a low affinity to GALR3, the residues in SPX were replaced with those in GAL, revealing that particular mutations such as Gln5 → Asn, Met7 → Ala, Lys11 → Phe, and Ala13 → Pro significantly decreased potencies toward GALR3 but not toward GALR2. Quadruple (Qu) mutation of these residues still retained potency to GALR2 but totally abolished the potency to both GALR3 and GALR1. The first amino acid modifications or D-Asn1 substitution significantly increased the stability when they are incubated in 100% fetal bovine serum. Intracerebroventricular administration of the mutant peptide with D-Asn1 and quadruple substitution (dN1-Qu) exhibited an anxiolytic effect in mice. Taken together, the GALR2-specific agonist with increased stability can greatly help delineation of GALR2-mediated functions and be very useful for treatments of anxiety disorder.
AB - The novel neuropeptide spexin (SPX) was discovered to activate galanin receptor 2 (GALR2) and 3 (GALR3) but not galanin receptor 1 (GALR1). Although GALR2 is known to display a function, particularly in anxiety, depression, and appetite regulation, the further determination of its function would benefit from a more stable and selective agonist that acts only at GALR2. In the present study, we developed a GALR2-specific agonist with increased stability in serum. As galanin (GAL) showed a low affinity to GALR3, the residues in SPX were replaced with those in GAL, revealing that particular mutations such as Gln5 → Asn, Met7 → Ala, Lys11 → Phe, and Ala13 → Pro significantly decreased potencies toward GALR3 but not toward GALR2. Quadruple (Qu) mutation of these residues still retained potency to GALR2 but totally abolished the potency to both GALR3 and GALR1. The first amino acid modifications or D-Asn1 substitution significantly increased the stability when they are incubated in 100% fetal bovine serum. Intracerebroventricular administration of the mutant peptide with D-Asn1 and quadruple substitution (dN1-Qu) exhibited an anxiolytic effect in mice. Taken together, the GALR2-specific agonist with increased stability can greatly help delineation of GALR2-mediated functions and be very useful for treatments of anxiety disorder.
UR - http://www.scopus.com/inward/record.url?scp=84959387174&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84959387174&partnerID=8YFLogxK
U2 - 10.1038/srep21453
DO - 10.1038/srep21453
M3 - Article
C2 - 26907960
AN - SCOPUS:84959387174
VL - 6
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 21453
ER -