Potassium channel subunits encoded by the KCNE gene family: physiology and pathophysiology of the MinK-related peptides (MiRPs).

Voltage-gated potassium channels provide tightly Controlled, ion-specific pathways across membranes and are key to the normal function of nerves muscles. They arise from the assembly of four pore-forming proteins called alpha-subunits. To attain the properties of native currents, alpha-subunits interact with additional molecules such as the mink-related peptides (MiRPs), single-transmembrane subunits encoded by the KCNE genes. Significantly, mutations in KCNE 1, 2 and 3 have been linked either to life-threatening cardiac arrhythmia or a disorder of skeletal muscle, familial periodic paralysis. The capacity of MiRPs to partner with multiple alpha-subunits in experimental cells appears to reflect still undiscovered roles for the KCNE-encoded peptides in vivo. Here, we consider these unique peptides in health disease and discuss future research directions

A superfamily of small potassium channel subunits: form and function of the MinK-related peptides (MiRPs).

MinK and MinK-related peptide I (MiRPI) are integral membrane peptides with a single transmembrane span. These peptides are active only when co-assembled with pore-forming K+ channel subunits and yet their role in normal ion channel behaviour is obligatory. In the resultant complex the peptides establish key functional attributes: gating kinetics, single-channel conductance, ion selectivity, regulation and pharmacology. Co-assembly is required to reconstitute channel behaviours like those observed in native cells. Thus, MinK/KvLQT1 and MiRPI/HERG complexes reproduce the cardiac currents called I(Ks) and I(Kr), respectively. Inherited mutations in KCNEI (encoding MinK) and KCNE2(encoding MiRPI) are associated with lethal cardiac arrhythmias. How these mutations change ion channel behaviour has shed light on peptide structure and function. Recently, KCNE3 and KCNE4 were isolated. In this review, we consider what is known and what remains controversial about this emerging superfamily

MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis.

The subthreshold, voltage-gated potassium channel of skeletal muscle is shown to contain MinK-related peptide 2 (MiRP2) and the pore-forming subunit Kv3.4. MiRP2-Kv3.4 channels differ from Kv3.4 channels in unitary conductance, voltage-dependent activation, recovery from inactivation, steady-state open probability, and block by a peptide toxin. Thus, MiRP2-Kv3.4 channels set resting membrane potential (RMP) and do not produce afterhyperpolarization or cumulative inactivation to limit action potential frequency. A missense mutation is identified in the gene for MiRP2 (KCNE3) in two families with periodic paralysis and found to segregate with the disease. Mutant MiRP2-Kv3.4 complexes exhibit reduced current density and diminished capacity to set RMP. Thus, MiRP2 operates with a classical potassium channel subunit to govern skeletal muscle function and pathophysiology

Establishing the Australian National Endometriosis Clinical and Scientific Trials (NECST) Registry: a protocol paper

Endometriosis is a common yet under-recognised chronic inflammatory disease, affecting 176 million women, trans and gender diverse people globally. The National Endometriosis Clinical and Scientific Trials (NECST) Registry is a new clinical registry collecting and tracking diagnostic and treatment data and patient-reported outcomes on people with endometriosis. The registry is a research priority action item from the 2018 National Action Plan for Endometriosis and aims to provide large-scale, national and longitudinal population-based data on endometriosis. Working groups (consisting of patients with endometriosis, clinicians and researchers) developing the NECST Registry data dictionary and data collection platform started in 2019. Our data dictionary was developed based on existing and validated questionnaires, tools, meta-data and data cubes – World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project, endometriosis CORE outcomes set, patient-reported outcome measures, the International Statistical Classification of Diseases-10th Revision Australian Modification diagnosis codes and Australian Government datasets: Australian Institute for Health and Welfare (for sociodemographic data), Medicare Benefits Schedule (for medical procedures) and the Pharmaceutical Benefits Scheme (for medical therapies). The resulting NECST Registry is an online, secure cloud-based database, prospectively collecting minimum core clinical and health data across eight patient and clinician modules and longitudinal data tracking disease life course. The NECST Registry has ethics approval (HREC/62508/ MonH-2020) and is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000987763)

Interaction between soluble and membrane-embedded potassium channel peptides monitored by Fourier transform infrared spectroscopy.

Recent studies have explored the utility of Fourier transform infrared spectroscopy (FTIR) in dynamic monitoring of soluble protein-protein interactions. Here, we investigated the applicability of FTIR to detect interaction between synthetic soluble and phospholipid-embedded peptides corresponding to, respectively, a voltage-gated potassium (Kv) channel inactivation domain (ID) and S4-S6 of the Shaker Kv channel (KV1; including the S4-S5 linker "pre-inactivation" ID binding site). KV1 was predominantly α-helical at 30°C when incorporated into dimyristoyl-l-α-phosphatidylcholine (DMPC) bilayers. Cooling to induce a shift in DMPC from liquid crystalline to gel phase reversibly decreased KV1 helicity, and was previously shown to partially extrude a synthetic S4 peptide. While no interaction was detected in liquid crystalline DMPC, upon cooling to induce the DMPC gel phase a reversible amide I peak (1633 cm(-1)) consistent with novel hydrogen bond formation was detected. This spectral shift was not observed for KV1 in the absence of ID (or vice versa), nor when the non-inactivating mutant V7E ID was applied to KV1 under similar conditions. Alteration of salt or redox conditions affected KV1-ID hydrogen bonding in a manner suggesting electrostatic KV1-ID interaction favored by a hairpin conformation for the ID and requiring extrusion of one or more KV1 domains from DMPC, consistent with ID binding to S4-S5. These findings support the utility of FTIR in detecting reversible interactions between soluble and membrane-embedded proteins, with lipid state-sensitivity of the conformation of the latter facilitating control of the interaction

An instability of higher-dimensional rotating black holes

We present the first example of a linearized gravitational instability of an asymptotically flat vacuum black hole. We study perturbations of a Myers-Perry black hole with equal angular momenta in an odd number of dimensions. We find no evidence of any instability in five or seven dimensions, but in nine dimensions, for sufficiently rapid rotation, we find perturbations that grow exponentially in time. The onset of instability is associated with the appearance of time-independent perturbations which generically break all but one of the rotational symmetries. This is interpreted as evidence for the existence of a new 70-parameter family of black hole solutions with only a single rotational symmetry. We also present results for the Gregory-Laflamme instability of rotating black strings, demonstrating that rotation makes black strings more unstable.Comment: 38 pages, 13 figure

The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

The original publication is available at http://www.jnrbm.com/content/10/1/12Includes bibliographyAbstract Background The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic disease associated with an improper hypertrophic response. Results The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls. Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only. Conclusions Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmiaPeer Reviewe

Warped black holes in 3D general massive gravity

We study regular spacelike warped black holes in the three dimensional general massive gravity model, which contains both the gravitational Chern-Simons term and the linear combination of curvature squared terms characterizing the new massive gravity besides the Einstein-Hilbert term. The parameters of the metric are found by solving a quartic equation constrained by an inequality that imposes the absence of closed timelike curves. Explicit expressions for the central charges are suggested by exploiting the fact that these black holes are discrete quotients of spacelike warped AdS(3) and a known formula for the entropy. Previous results obtained separately in topological massive gravity and in new massive gravity are recovered as special cases.Comment: 38 pages, 7 figures. v2: minor changes, added refs and an appendix on self-dual and null z-warped black hole