Verdict in the Smooth Muscle K
            <sub>ATP</sub>
            Channel Case

Dart, Caroline

doi:10.1161/hypertensionaha.114.03289

Cited by 1 publication

(1 citation statement)

References 12 publications

(16 reference statements)

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“…Graphic created with BioRender.com. (Aziz et al, 2014;Dart, 2014;Miki et al, 2002). Both global and vascular-specific K ir 6.1-KO mice are hypertensive, but global K ir 6.1 knockouts also display ST-elevation, indicative of acute myocardial ischaemia and are prone to sudden death.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterisation of functional K_ir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

Brennan,

Chen,

Makwana

et al. 2024

British J Pharmacology

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Background and PurposeThe canonical Kir6.2/SUR2A ventricular KATP channel is highly ATP‐sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of KATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second KATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active Kir6.1‐containing KATP channel in ventricular cardiomyocytes.Experimental ApproachPatch‐clamp recordings from rat ventricular myocytes in combination with well‐defined pharmacological modulators was used to characterise these newly identified K+ channels. Action potential recording, calcium (Fluo‐4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation.Key ResultsOur data show a ventricular K+ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with Kir6.1‐containing channels. These Kir6.1‐containing channels lack the ATP‐sensitivity of the canonical channels and are constitutively active.Conclusion and ImplicationsWe conclude there are two functionally distinct populations of ventricular KATP channels: constitutively active Kir6.1‐containing channels that play an important role in fine‐tuning the action potential and Kir6.2/SUR2A channels that activate with prolonged ischaemia to impart late‐stage protection against catastrophic ATP depletion. Further research is required to determine whether Kir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.

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Section: Discussionmentioning

confidence: 99%

Identification and characterisation of functional K_ir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

Brennan,

Chen,

Makwana

et al. 2024

British J Pharmacology

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Verdict in the Smooth Muscle K _ATP Channel Case

Cited by 1 publication

References 12 publications

Identification and characterisation of functional K_ir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

Identification and characterisation of functional K_ir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

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Verdict in the Smooth Muscle K ATP Channel Case

Cited by 1 publication

References 12 publications

Identification and characterisation of functional Kir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

Identification and characterisation of functional Kir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

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Verdict in the Smooth Muscle K _ATP Channel Case

Identification and characterisation of functional K_ir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

Identification and characterisation of functional K_ir6.1‐containing ATP‐sensitive potassium channels in the cardiac ventricular sarcolemmal membrane