Antidepressive effect of an inward rectifier K+ channel blocker peptide, tertiapin-RQ

Abstract

Renal outer medullary K+ channel, ROMK (Kir1.1, kcnj1) is expressed in the kidney and brain, but its role in the central nervous system remains unknown. Recent studies suggested an involvement of the ROMK channel in mental diseases. Tertiapin (TPN) is a European honey bee venom peptide and is reported to selectively block the ROMK channel. Here, we have chemically synthesized a series of mutated TPN peptides, including TPN-I8R and -M13Q (TPN-RQ), reported previously, and examined their blocking activity on the ROMK channel. Among 71 peptides tested, TPN-RQ was found to block the ROMK channel most effectively. Whole-cell patch-clamp recordings showed the essential roles of two disulfide bonds and the circular structure for the blockade activity. To examine the central role, we injected TPN-RQ intracerebroventricularly and examined the effects on depression- and anxiety-like behaviors in mice. TPN-RQ showed an antidepressive effect in tail-suspension and forced swim tests. The injection of TPN-RQ also enhanced the anxiety-like behavior in the elevated plus-maze and light/dark box tests and impaired spontaneous motor activities in balance beam and wheel running tests. Administration of TPM-RQ suppressed the anti-c-Fos immunoreactivity in the lateral septum, without affecting immunoreactivity in antidepressant-related nuclei, e.g. the dorsal raphe nucleus and locus coeruleus. TPN-RQ may exert its antidepressive effects through a different mechanism from current drugs.

Effect of chronic administration of ostruthin on depression-like behavior in chronically stressed mice

“…That study found that these effects involve the suppression of neural activities in a different nucleus, the lateral septum. In addition, we also demonstrated that the suppression of this nucleus is also involved in the antidepressive effect of ROMK (Kir1.1) channel blocker, tertiapin-RQ ( Okada et al, 2020 ). Thus, K⁺ channel modulators, e.g., ostruthin, are promising as antidepressants and should be further investigated for clinical application.…”

“…After tests on the 6th day, mice were subjected to SPT for 24 hrs, and sucrose solution/water consumption and food intake were measured. Each behavioral test was performed according to a method reported previously ( Joseph et al, 2018 , Okada et al, 2020 )…”

“…There are 76 types of channels in the channel families ( Kuang et al, 2015 ), each expressed in a nucleus-specific pattern in different neuronal nuclei ( Jenkinson, 2006 ). Modulations of these channels can therefore modulate neuronal activities in a nucleus-specific manner and thereby have therapeutic effects on depression ( Joseph et al, 2018 , Okada et al, 2020 , Okada and Ortiz, 2022 ). Indeed, previous research has demonstrated that the activation or inhibition of K⁺ channels can have antidepressant effects on mouse models of depression by modulating neural activity in specific nuclei.…”

Foodomics-based metabolites profiling of the Greek yogurt incorporated with unripened papaya peel powder

“…Enhanced propionyl carnitine is regarded as a biomarker of vitamin B-12 deficiency. Ostruthin has its role in anxiety and depression control which are common mental disorders ( Okada et al, 2020 ). Resorcinol is used in cosmetic pharmaceutical products as an anti-septic and infectant removal for the cure of skin problems and infections such as acne, seborrheic dermatitis, eczema, psoriasis, corns, calluses, and warts ( Fabri et al, 2023 ).…”

Grain Boundary Segregation Behavior and Thermodynamic Analysis Based on CALPHAD Method for B Added High Carbon Steel

“…[1][2][3][4] Because reduction of the grain boundary energy also increases the grain boundary strength, improved fatigue and impact strengths of structural steels by doping B have been reported because of grain boundary crack suppression. [5][6][7] Improvement of hardenability by doping B varies along with materials' production conditions and alloy compositions. Earlier reports have described that segregation of B on γ grain boundaries is influenced strongly by metallurgical phenomena in hot deformation: recrystallization generating new grain boundaries, diffusion of B to segregate on the newly generated grain boundaries, and formation of M 23 (C,B) 6 precipitates on the grain boundaries.…”