Molecular studies of ion channel function have primarily focused on the proteins themselves or on their interactions with other proteins or ions. G protein-gated K channels (KG) for example are thought to be directly activated by the betagamma subunits of GTP binding proteins (Gbetagamma subunits). Current models of KG channel activation involve G protein subunit separation (which renders them active) and interaction with the channel subunits. Our preliminary results suggest that the Gbetagamma subunit/KG channel interaction requires the presence of PIP2 in the membrane in order to manifest its effects on channel activity. This surprising result is accompanied by other effects directly attributable to PIP2, such as the MgATP-dependent sensitization of KG channels to gating by internal Na ions and possibly the MgATP-dependent rundown of G protein stimulation of KG channel activity. These results together with two recent reports on the related inwardly rectifying channel KATP and on the Na / Ca transporter (but not on Na channels or Na / K pumps) herald the potential of an unexplored area of research, crucial to the functional integrity of membrane proteins. Our proposal aims to study in detail the effects of lipids, and in particular phospholipids on KG channel function. The experiments outlined will test further the molecular basis and significance of the PIP2 effects on KG channel activity and the dependence of G protein subunit KG channel activation on the presence of PIP2. It has been proposed that the lipid effects are electrostatic in nature. We will test this hypothesis and seek to identify the basic residues in the channel sequence constituting sites of interaction with the anionic phospholipids. Phospholipids of the phosphoinositide cycle allow dynamic participation of lipids in signaling. We believe that a better appreciation of the molecular details of KG channel function afforded by this study will allow more successful manipulation of this atrial channel in the control of supraventricular arrhythmias. For example, our recent discovery of the MgATP-dependent sensitization of the atrial KG channel (KACh) to gating by internal Na ions allowed us to demonstrate that digitalis treatment causes atrial cells to activate KACh (due to the Na accumulation it causes), providing an important link to the long known effects of this drug on supraventricular rhythm.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL059949-01
Application #
2591639
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1998-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
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

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