The Mechanism of High-Output Cardiac Hypertrophy Arising From Potassium Channel Gain-of-Function in Cantú Syndrome.

Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (K) channels genes, and , is a characteristic feature of Cantú syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of cardiovascular remodeling in CS, is unknown. Using genome-edited mouse models of CS, we therefore sought to dissect the pathophysiological mechanisms linking K channel GoF to cardiac remodeling.

Structural mechanism for gating of a eukaryotic mechanosensitive channel of small conductance.

Mechanosensitive ion channels transduce physical force into electrochemical signaling that underlies an array of fundamental physiological processes, including hearing, touch, proprioception, osmoregulation, and morphogenesis. The mechanosensitive channels of small conductance (MscS) constitute a remarkably diverse superfamily of channels critical for management of osmotic pressure. Here, we present cryo-electron microscopy structures of a MscS homolog from Arabidopsis thaliana, MSL1, presumably in both the closed and open states.

Gating of human TRPV3 in a lipid bilayer.

The transient receptor potential cation channel subfamily V member 3 (TRPV3) channel plays a critical role in skin physiology, and mutations in TRPV3 result in the development of a congenital skin disorder, Olmsted syndrome. Here we describe multiple cryo-electron microscopy structures of human TRPV3 reconstituted into lipid nanodiscs, representing distinct functional states during the gating cycle. The ligand-free, closed conformation reveals well-ordered lipids interacting with the channel and two physical constrictions along the ion-conduction pore involving both the extracellular selectivity filter and intracellular helix bundle crossing.

Cryo-EM structures of the ATP release channel pannexin 1.

The plasma membrane adenosine triphosphate (ATP) release channel pannexin 1 (PANX1) has been implicated in many physiological and pathophysiological processes associated with purinergic signaling, including cancer progression, apoptotic cell clearance, inflammation, blood pressure regulation, oocyte development, epilepsy and neuropathic pain. Here we present near-atomic-resolution structures of human and frog PANX1 determined by cryo-electron microscopy that revealed a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule were exceptionally wide.

Three-dimensional facial morphology in Cantú syndrome.

Cantú syndrome (CS) was first described in 1982, and is caused by pathogenic variants in ABCC9 and KCNJ8 encoding regulatory and pore forming subunits of ATP-sensitive potassium (K ) channels, respectively. It is characterized by congenital hypertrichosis, osteochondrodysplasia, extensive cardiovascular abnormalities and distinctive facial anomalies including a broad nasal bridge, long philtrum, epicanthal folds, and prominent lips. Many genetic syndromes, such as CS, involve facial anomalies that serve as a significant clue in the initial identification of the respective disorder before clinical or molecular diagnosis are undertaken.

Structural and Biophysical Analysis of the CLCA1 VWA Domain Suggests Mode of TMEM16A Engagement.

The secreted protein calcium-activated chloride channel regulator 1 (CLCA1) utilizes a von Willebrand factor type A (VWA) domain to bind to and potentiate the calcium-activated chloride channel TMEM16A. To gain insight into this unique potentiation mechanism, we determined the 2.0-Å crystal structure of human CLCA1 VWA bound to Ca.

Cantú syndrome: Findings from 74 patients in the International Cantú Syndrome Registry.

Cantú syndrome (CS), first described in 1982, is caused by pathogenic variants in ABCC9 and KCNJ8, which encode the regulatory and pore forming subunits of ATP-sensitive potassium (K ) channels, respectively. Multiple case reports of affected individuals have described the various clinical features of CS, but systematic studies are lacking. To define the effects of genetic variants on CS phenotypes and clinical outcomes, we have developed a standardized REDCap-based registry for CS.

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity.

Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities.

Structural biology of thermoTRPV channels.

Essential for physiology, transient receptor potential (TRP) channels constitute a large and diverse family of cation channels functioning as cellular sensors responding to a vast array of physical and chemical stimuli. Detailed understanding of the inner workings of TRP channels has been hampered by a lack of atomic structures, though structural biology of TRP channels has been an enthusiastic endeavor since their molecular identification two decades ago. These multi-domain integral membrane proteins, exhibiting complex polymodal gating behavior, have been a challenge for traditional X-ray crystallography, which requires formation of well-ordered protein crystals.

ABCC9-related Intellectual disability Myopathy Syndrome is a K channelopathy with loss-of-function mutations in ABCC9.

Mutations in genes encoding K channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.

Glibenclamide treatment in a Cantú syndrome patient with a pathogenic ABCC9 gain-of-function variant: Initial experience.

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain-of-function mutations in the regulatory (SUR2) and pore-forming (Kir6.1) subunits of K channels, respectively, suggesting that channel-blocking sulfonylureas could be a viable therapy.

Beta-cell excitability and excitability-driven diabetes in adult Zebrafish islets.

Islet β-cell membrane excitability is a well-established regulator of mammalian insulin secretion, and defects in β-cell excitability are linked to multiple forms of diabetes. Evolutionary conservation of islet excitability in lower organisms is largely unexplored. Here we show that adult zebrafish islet calcium levels rise in response to elevated extracellular [glucose], with similar concentration-response relationship to mammalian β-cells.

The role of membrane excitability in pancreatic β-cell glucotoxicity.

Persistent hyperglycemia is causally associated with pancreatic β-cell dysfunction and loss of pancreatic insulin. Glucose normally enhances β-cell excitability through inhibition of K channels, opening of voltage-dependent calcium channels, increased [Ca], which triggers insulin secretion. Glucose-dependent excitability is lost in islets from K-knockout (K-KO) mice, in which β-cells are permanently hyperexcited, [Ca] is chronically elevated and insulin is constantly secreted.

Genetic Discovery of ATP-Sensitive K Channels in Cardiovascular Diseases.

The ATP-sensitive K (K) channels are hetero-octameric protein complexes comprising 4 pore-forming (Kir6.x) subunits and 4 regulatory sulfonylurea receptor (SURx) subunits. They are prominent in myocytes, pancreatic β cells, and neurons and link cellular metabolism with membrane excitability.

X-ray structures of the high-affinity copper transporter Ctr1.

Copper (Cu) is an essential trace element for growth and development and abnormal Cu levels are associated with anemia, metabolic disease and cancer. Evolutionarily conserved from fungi to humans, the high-affinity Cu transporter Ctr1 is crucial for both dietary Cu uptake and peripheral distribution, yet the mechanisms for selective permeation of potentially toxic Cu ions across cell membranes are unknown. Here we present X-ray crystal structures of Ctr1 from Salmo salar in both Cu-free and Cu-bound states, revealing a homo-trimeric Cu-selective ion channel-like architecture.

In vivo monitoring of intracellular Ca dynamics in the pancreatic β-cells of zebrafish embryos.

Assessing the response of pancreatic islet cells to glucose stimulation is important for understanding β-cell function. Zebrafish are a promising model for studies of metabolism in general, including stimulus-secretion coupling in the pancreas. We used transgenic zebrafish embryos expressing a genetically-encoded Ca sensor in pancreatic β-cells to monitor a key step in glucose induced insulin secretion; the elevations of intracellular [Ca].

Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension.

Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target.

Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients.

Polyamines and potassium channels: A 25-year romance.

Potassium channels that exhibit the property of inward rectification (Kir channels) are present in most cells. Cloning of the first Kir channel genes 25 years ago led to recognition that inward rectification is a consequence of voltage-dependent block by cytoplasmic polyamines, which are also ubiquitously present in animal cells. Upon cellular depolarization, these polycationic metabolites enter the Kir channel pore from the intracellular side, blocking the movement of K ions through the channel.

Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli.

Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases. During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane β-barrel translocation domain, a β-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2).

Elucidating a role for the cytoplasmic domain in the Mycobacterium tuberculosis mechanosensitive channel of large conductance.

Microbial survival in dynamic environments requires the ability to successfully respond to abrupt changes in osmolarity. The mechanosensitive channel of large conductance (MscL) is a ubiquitous channel that facilitates the survival of bacteria and archaea under severe osmotic downshock conditions by relieving excess turgor pressure in response to increased membrane tension. A prominent structural feature of MscL, the cytoplasmic C-terminal domain, has been suggested to influence channel assembly and function.

Contribution of systemic inflammation to permanence of K-induced neonatal diabetes in mice.

Gain-of-function (GOF) mutations in the ATP-sensitive potassium (K) channels cause neonatal diabetes. Despite the well-established genetic root of the disease, pathways modulating disease severity and treatment effectiveness remain poorly understood. Patient phenotypes can vary from severe diabetes to remission, even in individuals with the same mutation and within the same family, suggesting that subtle modifiers can influence disease outcome.

Cardiovascular consequences of KATP overactivity in Cantu syndrome.

Cantu syndrome (CS) is characterized by multiple vascular and cardiac abnormalities including vascular dilation and tortuosity, systemic hypotension, and cardiomegaly. The disorder is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) ATP-sensitive potassium (KATP) channel subunits.

Macrophage angiotensin II type 2 receptor triggers neuropathic pain.

Peripheral nerve damage initiates a complex series of structural and cellular processes that culminate in chronic neuropathic pain. The recent success of a type 2 angiotensin II (Ang II) receptor (AT2R) antagonist in a phase II clinical trial for the treatment of postherpetic neuralgia suggests angiotensin signaling is involved in neuropathic pain. However, transcriptome analysis indicates a lack of AT2R gene () expression in human and rodent sensory ganglia, raising questions regarding the tissue/cell target underlying the analgesic effect of AT2R antagonism.