Korean J Physiol Pharmacol.  2022 Jan;26(1):25-36. 10.4196/kjpp.2022.26.1.25.

Carbon monoxide activation of delayed rectifier potassium currents of human cardiac fibroblasts through diverse pathways

• Bae H
• Kim T
• Lim I

• KMID: 2524517
• DOI: http://doi.org/10.4196/kjpp.2022.26.1.25

Abstract

To identify the effect and mechanism of carbon monoxide (CO) on delayed rectifier K⁺ currents (I_K) of human cardiac fibroblasts (HCFs), we used the wholecell mode patch-clamp technique. Application of CO delivered by carbon monoxidereleasing molecule-3 (CORM3) increased the amplitude of outward K⁺ currents, and diphenyl phosphine oxide-1 (a specific I_K blocker) inhibited the currents. CORM3-induced augmentation was blocked by pretreatment with nitric oxide synthase blockers (L-NG-monomethyl arginine citrate and L-NG-nitro arginine methyl ester). Pretreatment with KT5823 (a protein kinas G blocker), 1H-[1,-2,-4] oxadiazolo-[4,-3-a] quinoxalin-1-on (ODQ, a soluble guanylate cyclase blocker), KT5720 (a protein kinase A blocker), and SQ22536 (an adenylate cyclase blocker) blocked the CORM3 stimulating effect on I_K . In addition, pretreatment with SB239063 (a p38 mitogen-activated protein kinase [MAPK] blocker) and PD98059 (a p44/42 MAPK blocker) also blocked the CORM3’s effect on the currents. When testing the involvement of S-nitrosylation, pretreatment of N-ethylmaleimide (a thiol-alkylating reagent) blocked CO-induced I_K activation and DL-dithiothreitol (a reducing agent) reversed this effect. Pretreatment with 5,10,15,20-tetrakis(1-methylpyridinium-4-yl)-21H,23H porphyrin manganese (III) pentachloride and manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (superoxide dismutase mimetics), diphenyleneiodonium chloride (an NADPH oxidase blocker), or allopurinol (a xanthine oxidase blocker) also inhibited CO-induced I_K activation. These results suggest that CO enhances I_K in HCFs through the nitric oxide, phosphorylation by protein kinase G, protein kinase A, and MAPK, S-nitrosylation and reduction/oxidation (redox) signaling pathways.

Keyword

Carbon monoxide; Delayed rectifier K⁺ currents; Nitric oxide; Protein kinase; Signaling

Figure

• 

  Fig. 1 Carbon monoxide (CO) increases delayed rectifier K+ currents (IK) of human cardiac fibroblasts (HCFs). Original recordings of the K+ currents were obtained by repeated voltage step depolarization from −80 to +50 mV for 400 ms duration (holding potential was –80 mV) by whole-cell mode patch clamp recordings. (A) Representative outward K+ currents show the changes before (control) and after application of (A) carbon monoxide-releasing molecule-3 (CORM3, a CO donor, 10 μM) or (B) iCORM3 (inactive CORM3, 10 μM). The currents were blocked by diphenyl phosphine oxide-1 (DPO-1, a blocker of the delayed rectifier K+ channel and the Kv1.5 channel, 1 μM). (C) Summarized current–voltage (I–V) curves of steady-state currents for the effects of CORM3, iCORM3, and DPO-1. (D) Bar graphs showing the current density changes of the K+ currents at +30 mV regarding the effects of CORM3, iCORM3, and DPO-1 (n = 7, each). (E) Concentration-dependent activation curve of IK by CORM3. The solid line shows the fit based on a standard dose-response relationship, which yielded an estimated half maximal effective concentration (EC50) of 11.38 μM for CORM3. Values are mean ± SEM, *p < 0.05, **p < 0.01, and ***p < 0.001 compared to control (n = 7, each).

• 

  Fig. 2 Nitric oxide synthase (NOS) blockers inhibits carbon monoxide (CO)–induced activation of delayed rectifier K+ currents (IK) in human cardiac fibroblasts (HCFs). Currents are obtained in which cells were repeatedly depolarized from −80 mV to +50 mV (400 ms duration). carbon monoxide-releasing molecule-3 (CORM3) was applied either to untreated cells or to cells pretreated for 20 min with NOS blockers. (A) Representative original recordings of IK show the CORM3 (10 μM) effect after pretreatment of L-NG-monomethyl arginine citrate (L-NMMA, 100 μM) for 20 min. (B) Summarized current–voltage (I–V) relationship curves for IK and (C) bar graphs for the summary of current density changes of IK (at +30 mV) also show the effect of CORM3 (10 μM) on IK after pretreatment of L-NMMA (100 μM). (D) Representative original recordings of IK. (E) Summarized I–V relationship curves of IK, and (F) bar graphs for the summary of current density changes of IK (at +30 mV) also show the CORM3 (10 μM) effect on IK after L-NG-nitroarginine methyl ester (L-NAME, 100 μM) pretreatment (n = 7 each). Values are mean ± SEM (n = 7 each).

• 

  Fig. 3 cGMP and cAMP signaling pathways involved in carbon monoxide (CO)–induced activation of delayed rectifier K+ currents (IK) in human cardiac fibroblasts (HCFs). Summarized current–voltage (I–V) curves from –60 mV to +50 mV show the effects of carbon monoxide-releasing molecule-3 (CORM3, 10 μM) on IK after pretreatments with (A) KT5823 (a PKG blocker, 1 μM) or (B) ODQ (a soluble guanylate cyclase blocker, 1 μM) (n = 7 each). (C) Bar graphs show summarizing current density changes for the CORM3 effects on IK after pretreatments with KT5823 or ODQ (at +30 mV). Summarized I–V curves for the effects of CORM3 on IK after pre-incubation with (D) KT5720 (a PKA blocker, 1 μM) or (E) SQ22536 (an adenylate cyclase blocker, 1 μM). (F) Bar graphs show current density changes at +30 mV for the effects of CORM3 on IK after pre-incubation with KT5720 or SQ22536 (n = 7 each). Values are mean ± SEM.

• 

  Fig. 4 S-nitrosylation involves carbon monoxide (CO)–induced activation of delayed rectifier K+ currents (IK) in human cardiac fibroblasts (HCFs). (A) Original recordings for the effect of carbon monoxide-releasing molecule-3 (CORM3, 10 μM) on IK after pretreatment with N-ethylmaleimide (NEM, a thiol-alkylating reagent, 0.5 mM) at +30 mV stimulation. (B) Summarized current–voltage (I–V) curves for the effect of CORM3 (10 μM) on IK after pretreatment with NEM (0.5 mM). (C) Bar graphs showing the current density changes for the CORM3 effects on IK after pretreatment with NEM (at +30 mV, n = 7 each). (D–F) The reversing effect of DL-dithiothreitol (DTT, a reducing agent, 5 mM) for CORM3-induced activation on IK (*p < 0.05 compared to control, #p < 0.05 compared to CORM3, n = 7 each).

• 

  Fig. 5 Effect of mitogen-activated protein kinase (MAPK) and redox signaling pathways on carbon monoxide (CO)-induced activation of delayed rectifier K+ currents (IK) in human cardiac fibroblasts (HCFs). (A, B) Summarized current–voltage (I–V) curves and (C) bar graphs of current density changes for the carbon monoxide-releasing molecule-3 (CORM3, 10 μM) effects on IK after pretreatment with SB239063 (a p38 MAPK inhibitor, 10 μM) or PD98059 (a p44/42 MAPK inhibitor, 10 μM), n = 7 (each). (D, E) Summarized I–V curves and (F) bar graphs for the effects of 10 μM CORM3 on IK after pretreatments with superoxide dismutase mimetics; MnTMPYP (50 μM) or MnTBAP (10 μM), n = 7 (each). Summarized I–V curves and bar graphs of current density changes for the effects of CORM3 on IK after (G) diphenylene iodonium (DPI, a NADPH oxidase inhibitor, 3 μM, n = 7) or (H) allopurinol (a xanthine oxidase inhibitor, 1 μM, n = 7).

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