# The mechanism of cardio-protection from a sulfonylurea receptor isoform 2 splice variant (SUR2A-55) and its role in regulating ROMK activity, the putative mitochondrial ATP sensitive potassium channel

> **NIH VA IK2** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2021 · —

## Abstract

Candidate: I am a staff cardiologist at the William S. Middleton Memorial VA and Assistant Professor of Medicine
at the University of Wisconsin School of Medicine and Public Health. I obtained my MD from Northwestern
University and completed internal medicine residency at Johns Hopkins Hospital and cardiology fellowship at
the University of Pittsburgh. During my fellowship training I dedicated additional time in the laboratory of Dr.
Ferhaan Ahmad to study mechanisms of genetic cardiomyopathies, which eventually led to the study of
cardioprotective mechanisms in ischemia reperfusion injury due to my clinical interest in interventional
cardiology. I was recruited to the William S. Middleton Memorial VA and University of Wisconsin to provide
increased interventional cardiology coverage to Veteran patients but to also continue my work in cardioprotection
with start-up funds, institutional mentorship and laboratory resources.
Research Project: Activation of mitochondrial K+ flux confers cardioprotection in models of ischemic injury. Of
the potential channels that modulate K+ flux, the putative mitochondrial ATP-sensitive potassium channel
(mitoKATP) is most closely related to cardioprotection. However the molecular identity of mitoKATP is unknown and
represents a critical gap in knowledge to discover therapies that target the mitochondrial K+ cycle. Prior studies
and my preliminary data provide evidence for a short 55 kDa splice variant of the sulfonylurea receptor 2A
(SUR2A-55) that targets mitochondria, regulates mitoKATP activity, enables increased glucose metabolism and
protects the heart from ischemia-reperfusion injury when overexpressed. In addition, prior studies and my
preliminary data suggest a role for the renal outer medullary K+ channel (ROMK) in mitochondrial ATP sensitive
K+ transport and cardioprotection. In this proposal we hypothesize that SUR2A-55 combines with ROMK2 to
form a cardiac mitoKATP channel that blocks ischemic injury by activating the mitochondrial K+ cycle
and enhancing glucose metabolism. By targeting both mitochondria and myocardial substrate utilization,
SUR2A-55 represents a novel target in the treatment of ischemic heart disease. We propose to investigate this
hypothesis with three specific aims. Specific Aim 1: Determine if SUR2A-55 associates with ROMK in cardiac
mitochondria to form a mitochondrial K+ channel. Immuno-affinity enrichment coupled with mass spectroscopy
will be used to examine potential associations between SUR2A-55 and ROMK2. Specific Aim 2: Determine if
the loss of function of cardiac ROMK prevents activation of mitoKATP and cardioprotection. We will test whether
pharmacologic inhibition or genetic knockdown of ROMK prevents activation of mitoKATP and protection from
ischemic preconditioning. Specific Aim 3: Examine how TGSUR2A-55 mice utilize metabolic substrates and
whether a preference for glucose utilization over fatty acids during ischemia contributes to cardioprotection.
Glucose and fatty ...

## Key facts

- **NIH application ID:** 10013619
- **Project number:** 1IK2BX004614-01A1
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Mohun Ramratnam
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013619

## Citation

> US National Institutes of Health, RePORTER application 10013619, The mechanism of cardio-protection from a sulfonylurea receptor isoform 2 splice variant (SUR2A-55) and its role in regulating ROMK activity, the putative mitochondrial ATP sensitive potassium channel (1IK2BX004614-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10013619. Licensed CC0.

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