Kir3 or GIRK (G protein gated inwardly rectifying K+) channels are activated by the vagus nerve to control heart rate. They are critical determinants of heart rate variability (HRV), an index of cardiac health, endowing the heart with the adaptability it needs to make rapid adjustments in heart rate. GIRK channels are attractive drug targets against atrial fibrillation (AF), the most common arrhythmia whose prevalence increases with age with an increased risk of mortality, stroke and myocardial infarction. The lack of specificity of the current antiarrhythmics used poses significant risk for ventricular side effects. This makes rather attractive targets expressed predominantly in the atria. Overactivity of cardiac GIRK channels has been implicated under the oxidative stress conditions characteristic of aging through a dysregulation of Protein Kinase C (PKC) enzymes, such as the increase in activity of the novel PKCe. Yet, even though full inhibitors of GIRK activity could reverse AF, they would also inhibit HRV, a side effect detrimental to cardiac health. Thus, the need for specific partial inhibitors that reverse the PKC-mediated channel activation but do not inhibit the vital functions of the channel is an unmet medical need. In this proposal, we investigate the mechanism by which PKC-dependent phosphorylation affects activity and show that it allosterically affects the interactions of the channel with PIP2, the master regulator of membrane protein function. We identify one phosphorylation site used by PKCe to stimulate channel activity and propose to determine all the sites involved and identify the gates they allosterically couple with to cause channel activation. In parallel, we have developed powerful structural computational models that allow us to test the action of small molecule inhibitors, which also allosterically control distinct channel gates via PIP2. In this proposal, we aim to set the stage in coupling the molecular insights of small molecule regulators of activity to specifically reverse the PKC-mediated overstimulation of channel activity. Our small molecule inhibitors will be tested in transgenic models of PKC-mediated AF with the goal to dial down the aberrant activity enough to correct the AF problem without compromising cardiac health.

Public Health Relevance

Overactivity of the atrial potassium channel used by the vagus nerve to regulate heart rate has been found to underlie the most prevalent arrhythmia in the aging population, atrial fibrillation. Based on powerful structural dynamic models of the channels, we explore the mechanism by which the channel activity is increased and design small molecule inhibitors to counteract this effect without compromising the vital functions of this channel.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Tjurmina, Olga A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northeastern University
Schools of Pharmacy
United States
Zip Code
Corbin-Leftwich, Aaron; Small, Hannah E; Robinson, Helen H et al. (2018) A Xenopus oocyte model system to study action potentials. J Gen Physiol 150:1583-1593
Ha, Junghoon; Xu, Yu; Kawano, Takeharu et al. (2018) Hydrogen sulfide inhibits Kir2 and Kir3 channels by decreasing sensitivity to the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). J Biol Chem 293:3546-3561
Delgado-Ramírez, Mayra; De Jesús-Pérez, José J; Aréchiga-Figueroa, Iván A et al. (2018) Regulation of Kv2.1 channel inactivation by phosphatidylinositol 4,5-bisphosphate. Sci Rep 8:1769
Fribourg, Miguel; Logothetis, Diomedes E; González-Maeso, Javier et al. (2017) Elucidation of molecular kinetic schemes from macroscopic traces using system identification. PLoS Comput Biol 13:e1005376
Tobelaim, William S; Dvir, Meidan; Lebel, Guy et al. (2017) Ca2+-Calmodulin and PIP2 interactions at the proximal C-terminus of Kv7 channels. Channels (Austin) 11:686-695
Tobelaim, William Sam; Dvir, Meidan; Lebel, Guy et al. (2017) Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv7.1 channel. Proc Natl Acad Sci U S A 114:E869-E878
Tang, Qiong-Yao; Zhang, Fei-Fei; Xu, Jie et al. (2016) Epilepsy-Related Slack Channel Mutants Lead to Channel Over-Activity by Two Different Mechanisms. Cell Rep 14:129-139
Li, Junwei; Xiao, Shaoying; Xie, Xiaoxiao et al. (2016) Three pairs of weak interactions precisely regulate the G-loop gate of Kir2.1 channel. Proteins 84:1929-1937
Deng, Wu; Mahajan, Rahul; Baumgarten, Clive M et al. (2016) The ICl,swell inhibitor DCPIB blocks Kir channels that possess weak affinity for PIP2. Pflugers Arch 468:817-24
Meng, Xuan-Yu; Liu, Shengtang; Cui, Meng et al. (2016) The Molecular Mechanism of Opening the Helix Bundle Crossing (HBC) Gate of a Kir Channel. Sci Rep 6:29399

Showing the most recent 10 out of 63 publications