Acute exposure of methylglyoxal leads to activation of KATP channels expressed in HEK293 cells

Abstract

Diabetes is characterized by hyperglycemia and excessive production of metabolites. One of these metabolites is the highly reactive carbonyl, methylglyoxal (MGO). MGO can readily react with biomolecules leading to cellular dysfunction. Here we showed that acute MGO application led to a dose-dependent activation of KATP channels, a major vascular tone regulator and a critical pharmacological target for treating diabetes. Both Kir6.1 and Kir6.2 containing KATP channels were targeted by MGO in a SUR subunit independent manner. Single channel analysis showed that MGO mediated KATP channel activation via enhancement of channel open probability, leaving the channel conductance unaltered. This modulation appeared to be due to the direct interaction of MGO with the KATP channel, without the need for additional cell signaling pathways. Moreover, MGO mediated KATP channel activity was completely reversed with bath solution washout. Taken together, these data suggest that acute exposure to MGO activates KATP channels through direct, non-covalent and reversible interactions with the Kir6.x subunit, suggest a potential target for pharmacological intervention towards vascular complications of diabetes.

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

“…Such observations occur through ion channel modulation, namely the large conductance Ca 2+ ‐activated K + channel (BK ca ) . Such differences were also validated by Yang et al., which observed stimulation of the KATP channel of vascular smooth muscle cells after acute MG exposure, but inhibition after chronic exposure . Such results show that MG‐induced modification of ionic channel structure may trigger acute changes in vessel tone, but long‐term inhibition that, along with decreased NO bioavailability, hampers vessel relaxation.…”

The role of serum methylglyoxal on diabetic peripheral and cardiovascular autonomic neuropathy: the ADDITION Denmark study

“…Our findings might point to a positive association between methylglyoxal and parasympathetic activity because there is a trend towards a positive association between methylglyoxal and all heart rate variability indices. Methylglyoxal has been show to facilitate an increased efflux of potassium through transmembrane potassium ion channels in human cell cultures . In theory, methylglyoxal might modify muscarinic potassium ion channels regulated by the parasympathetic nervous system in cardiac pacemaker cells increasing the parasympathetic influence of the heart.…”

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging

“…Furthermore, the RAGE-mediated activation of NF-ĸB increases the renin-angiotensin levels and blood pressure in rats treated with MGO [164]. At vascular smooth muscle cell level, MGO modifies ion channel structure, which results in acute changes in vessel tone but long-term inhibition that hinders vessel relaxation [165,166].…”