Potassium Channelopathies in Pulmonary Arterial Hypertension

A debilitating illness, pulmonary arterial hypertension (PAH) arises from deleterious remodeling of pulmonary arterioles, leading to increased pulmonary artery pressure, a rise in pulmonary vascular resistance, right sided heart failure and death. The pathogenesis of the disease is incompletely understood; however, certain established pathological features have guided medical treatments to improve mortality rates. For instance, an imbalance of vasoconstrictor molecules, such as endothelin-1, to vasodilator compounds, such as nitric oxide, contributes to excessive pulmonary arterial constriction, and a propensity for pulmonary arterial smooth muscle and endothelial cell proliferation. Therapeutic strategies may aim to restore this imbalance with the use of endothelin receptor antagonists, prostacyclin analogs, and other vasodilating agents. Mutations in the BMPR2 gene, the most common genetic cause of PAH, leads to aberrant TGF-ß signaling, which promotes uncontrollable cell proliferation and pathological changes in pulmonary arterioles. Genetic studies have revealed PAH-associated mutations in several other genes within the TGF-ß signaling pathway. More recently, our research group discovered loss-of-function mutations in the KCNK3 gene encoding the KCNK3 two-pore domain potassium channel in patients with idiopathic and familial PAH. KCNK3 (also referred to as TASK-1, or K2P3.1) represents the first ion channelopathy as a cause of PAH. KCNK3 is expressed in human pulmonary artery smooth muscle and endothelial cells. Loss of KCNK3 channel currents leads to membrane depolarization and predisposes to deleterious pulmonary arterial remodeling. Chapter 1 of my thesis explores the impact of KCNK3 mutations on potassium channel function in cellular models of heterozygous conditions, as all patients with PAH-associated KCNK3 mutations in our study were heterozygous at the KCNK3 gene locus. Furthermore, we explored function of mutant and non-mutant KCNK3 channels in cultured human pulmonary artery smooth muscle cells to better define the electrophysiological consequence of KCNK3 dysfunction, and used a KCNK3-activating pharmacological agent, ONO-RS-082, to gauge the therapeutic potential of KCNK3 as a pharmacological target in PAH. Moreover, the study of KCNK3 channel activity when assembled with the closely related KCNK9 channel provided a platform for exploring the lung-specific phenotype in patients with heterozygous KCNK3 mutations, despite widespread tissue expression KCNK3 in the body. In Chapter 2 of my thesis work, the discovery of a second potassium channelopathy in PAH is characterized. Heterozygous mutations in the ABCC8 gene, encoding the sulfonylurea receptor 1 (SUR1) protein, were found in pediatric and adult patients with idiopathic and familial PAH. SUR1, a beta subunit of the ATP-sensitive potassium channel (KATP), assembles with the pore-forming Kir6.2 alpha subunit to form KATP, a channel sensitive to inhibition by intracellular ATP. At the plasma membrane, KATP inwardly rectifying potassium currents contribute to the resting potential, and may play a pathophysiological role in PAH via dysfunction in pulmonary artery smooth muscle and/or endothelial cells. In this chapter, eight ABCC8 mutations associated with PAH were functionally characterized, and pharmacological agents were employed to examine the therapeutic potential in targeting SUR1-containing KATP channels in PAH. Altogether, the research presented in this dissertation identifies and explores potassium channel dysfunction as a pathogenic mechanism in PAH, due to heterozygous genetic mutations in KCNK3 and ABCC8. Evidence of restoration of mutant KCNK3 and KATP channel function by pharmacological agents suggests that targeting potassium channels as a therapeutic strategy may alleviate the severe morbidity and mortality burden in patients with PAH

Spin-orbit driven Peierls transition and possible exotic superconductivity in CsW2_{2}O6_{6}

We study \textit{ab initio} a pyrochlore compound, CsW$_{2}$O$_{6}$, which exhibits a yet unexplained metal-insulator transition. We find that (1) the reported low-$T$ structure is likely inaccurate and the correct structure has a twice larger cell; (2) the insulating phase is not of a Mott or dimer-singlet nature, but a rare example of a 3D Peierls transition, with a simultaneous condensation of three density waves; (3) spin-orbit interaction plays a crucial role, forming well-nested bands. The high-$T$ (HT) phase, if stabilized, could harbor a unique $e_{g}+ie_{g}$ superconducting state that breaks the time reversal symmetry, but is not chiral. This state was predicted in 1999, but never observed. We speculate about possible ways to stabilize the HT phase while keeping the conditions for superconductivity

Characteristics of oxygen isotope substitutions in the quasiparticle spectrum of Bi2_2Sr2_2CaCu2_2O8+δ_{8+\delta}

There is an ongoing debate about the nature of the bosonic excitations responsible for the quasiparticle self energy in high temperature superconductors -- are they phonons or spin fluctuations? We present a careful analysis of the bosonic excitations as revealed by the `kink' feature at 70 meV in angle resolved photoemission data using Eliashberg theory for a d-wave superconductor. Starting from the assumption that nodal quasiparticles are not coupled to the $(\pi,\pi)$ magnetic resonance, the sharp structure at $70$meV can be assigned to phonons. We find that not only can we account for the shifts of the kink energy seen on oxygen isotope substitution but also get a quantitative estimate of the fraction of the area under the electron-boson spectral density which is due to phonons. We conclude that for optimally doped Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$ phonons contribute $\sim 10$% and non-phononic excitations $\sim 90$%.Comment: 6 pages, 3 figure

Ab initio lattice dynamics and electron-phonon coupling of Bi(111)

We present a comprehensive ab initio study of structural, electronic, lattice dynamical and electron-phonon coupling properties of the Bi(111) surface within density functional perturbation theory. Relativistic corrections due to spin-orbit coupling are consistently taken into account. As calculations are carried out in a periodic slab geometry, special attention is given to the convergence with respect to the slab thickness. Although the electronic structure of Bi(111) thin films varies significantly with thickness, we found that the lattice dynamics of Bi(111) is quite robust and appears converged already for slabs as thin as 6 bilayers. Changes of interatomic couplings are confined mostly to the first two bilayers, resulting in super-bulk modes with frequencies higher than the optic bulk spectrum, and in an enhanced density of states at lower frequencies for atoms in the first bilayer. Electronic states of the surface band related to the outer part of the hole Fermi surfaces exhibit a moderate electron-phonon coupling of about 0.45, which is larger than the coupling constant of bulk Bi. States at the inner part of the hole surface as well as those forming the electron pocket close to the zone center show much increased couplings due to transitions into bulk projected states near Gamma_bar. For these cases, the state dependent Eliashberg functions exhibit pronounced peaks at low energy and strongly deviate in shape from a Debye-like spectrum, indicating that an extraction of the coupling strength from measured electronic self-energies based on this simple model is likely to fail.Comment: 30 pages, 11 figure

Lattice dynamics and electron-phonon coupling in transition metal diborides

The phonon density-of-states of transition metal diborides TMB2 with TM = Ti, V, Ta, Nb and Y has been measured using the technique of inelastic neutron scattering. The experimental data are compared with ab initio density functional calculations whereby an excellent agreement is registered. The calculations thus can be used to obtain electron-phonon spectral functions within the isotropic limit. A comparison to similar data for MgB2 and AlB2 which were subject of prior publications as well as parameters important for the superconducting properties are part of the discussion.Comment: 4 pages, 3 figure

Properties of the phonon-induced pairing interaction in YBa2_2Cu3_3O7_7 within the local density approximation

The properties of the phonon-induced interaction between electrons are studied using the local density approximation (LDA). Restricting the electron momenta to the Fermi surface we find generally that this interaction has a pronounced peak for large momentum transfers and that the interband contributions between bonding and antibonding band are of the same magnitude as the intraband ones. Results are given for various symmetry averages of this interaction over the Fermi surface. In particular, we find that the dimensionless coupling constant in the d-wave channel $\lambda^d$, relevant for superconductivity, is only 0.022, i.e., even about ten times smaller than the small value of the s-wave channel. Similarly, the LDA contribution to the resistivity is about a factor 10 times smaller than the observed resistivity suggesting that phonons are not the important low-energy excitations in high-T$_c$ oxides.Comment: 6 pages, 7 figure

Interplay between charge-lattice interaction and strong electron correlations in cuprates: phonon anomaly and spectral kinks

We investigate the interplay between strong electron correlations and charge-lattice interaction in cuprates. The coupling between half breathing bond stretching phonons and doped holes in the t-t'-J model is studied by limited phonon basis exact diagonalization method. Nonadiabatic electron-phonon interaction leads to the splitting of the phonon spectral function at half-way to the zone boundary at $\vec{q}_s=\{(\pm \pi / 2, 0), (0, \pm \pi / 2) \}$ and to low energy kink feature in the electron dispersion, in agreement with experimental observations. Another kink due to strong electron correlation effects is observed at higher energy, depending on the strength of the charge-lattice coupling.Comment: 4 pages, 3 figure