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Published By American Physiological Society

1522-1210, 0031-9333

Author(s):  
David B. Hill ◽  
Brian Button ◽  
Michael Rubinstein ◽  
Richard C. Boucher

The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., CF, COPD, NCFB, and PCD. A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.


Author(s):  
Stephan E. Lehnart ◽  
Xander H.T. Wehrens

Junctophilins (JPHs) comprise a family of structural proteins that connect the plasma membrane to intracellular organelles such as the endo/sarcoplasmic reticulum. Tethering of these membrane structures results in the formation of highly organized subcellular junctions that play important signaling roles in all excitable cell types. There are four JPH isoforms, expressed primarily in muscle and neuronal cell types. Each JPH protein consists of 6 'membrane occupation and recognition nexus' (MORN) motifs, a joining region connecting these to another set of 2 MORN motifs, a putative alpha-helical region, a divergent region exhibiting low homology between JPH isoforms, and a carboxy-terminal transmembrane region anchoring into the ER/SR membrane. JPH isoforms play essential roles in developing and maintaining subcellular membrane junctions. Conversely, inherited mutations in JPH2 cause hypertrophic or dilated cardiomyopathy, while trinucleotide expansions in the JPH3 gene cause Huntington Disease-Like 2. Loss of JPH1 protein levels can cause skeletal myopathy, while loss of cardiac JPH2 levels causes heart failure and atrial fibrillation, among other disease. This review will provide a comprehensive overview of the JPH gene family, phylogeny, and evolutionary analysis of JPH genes and other MORN domain proteins. JPH biogenesis, membrane tethering, and binding partners will be discussed, as well as functional roles of JPH isoforms in excitable cells. Finally, potential roles of JPH isoform deficits in human disease pathogenesis will be reviewed.


2022 ◽  
Vol 102 (1) ◽  
pp. 411-454
Author(s):  
Bart Tummers ◽  
Douglas R. Green

The coevolution of host-pathogen interactions underlies many human physiological traits associated with protection from or susceptibility to infections. Among the mechanisms that animals utilize to control infections are the regulated cell death pathways of pyroptosis, apoptosis, and necroptosis. Over the course of evolution these pathways have become intricate and complex, coevolving with microbes that infect animal hosts. Microbes, in turn, have evolved strategies to interfere with the pathways of regulated cell death to avoid eradication by the host. Here, we present an overview of the mechanisms of regulated cell death in Animalia and the strategies devised by pathogens to interfere with these processes. We review the molecular pathways of regulated cell death, their roles in infection, and how they are perturbed by viruses and bacteria, providing insights into the coevolution of host-pathogen interactions and cell death pathways.


Author(s):  
Rose Ellen Dixon ◽  
Manuel F. Navedo ◽  
Marc D Binder ◽  
L. Fernando Santana

Ion channels play a central role in the regulation of nearly every cellular process. Dating back to the classic 1952 Hodgkin-Huxley model of the generation of the action potential, ion channels have always been thought of as independent agents. A myriad of recent experimental findings exploiting advances in electrophysiology, structural biology, and imaging techniques, however, have posed a serious challenge to this long-held axiom as several classes of ion channels appear to open and close in a coordinated, cooperative manner. Ion channel cooperativity ranges from variable-sized oligomeric cooperative gating in voltage-gated, dihydropyridine-sensitive Cav1.2 and Cav1.3 channels to obligatory dimeric assembly and gating of voltage-gated Nav1.5 channels. Potassium channels, transient receptor potential channels, hyperpolarization cyclic nucleotide-activated channels, ryanodine receptors (RyRs), and inositol trisphosphate receptors (IP3Rs) have also been shown to gate cooperatively. The implications of cooperative gating of these ion channels range from fine tuning excitation-contraction coupling in muscle cells to regulating cardiac function and vascular tone, to modulation of action potential and conduction velocity in neurons and cardiac cells, and to control of pace-making activity in the heart. In this review, we discuss the mechanisms leading to cooperative gating of ion channels, their physiological consequences and how alterations in cooperative gating of ion channels may induce a range of clinically significant pathologies.


Author(s):  
Joanne F Garbincius ◽  
John W. Elrod

The uptake of calcium into and extrusion of calcium from the mitochondrial matrix is a fundamental biological process that has critical effects on cellular metabolism, signaling, and survival. Disruption of mitochondrial calcium (mCa2+) cycling is implicated in numerous acquired diseases such as heart failure, stroke, neurodegeneration, diabetes, and cancer, and is genetically linked to several inherited neuromuscular disorders. Understanding the mechanisms responsible for mCa2+ exchange therefore holds great promise for the treatment of these diseases. The past decade has seen the genetic identification of many of the key proteins that mediate mitochondrial calcium uptake and efflux. Here, we present an overview of the phenomenon of mCa2+ transport, and a comprehensive examination of the molecular machinery that mediates calcium flux across the inner mitochondrial membrane: the mitochondrial uniporter complex (consisting of MCU, EMRE, MICU1, MICU2, MICU3, MCUB, and MCUR1), NCLX, LETM1, the mitochondrial ryanodine receptor, and the mitochondrial permeability transition pore. We then consider the physiological implications of mCa2+ flux and evaluate how alterations in mCa2+ homeostasis contribute to human disease. This review concludes by highlighting opportunities and challenges for therapeutic intervention in pathologies characterized by aberrant mCa2+ handling and by summarizing critical unanswered questions regarding the biology of mCa2+ flux.


Author(s):  
Katrina F. Ostrom ◽  
Justin E. LaVigne ◽  
Tarsis F. Brust ◽  
Roland Seifert ◽  
Carmen W Dessauer ◽  
...  

Adenylyl cyclases (ACs) catalyze the conversion of ATP to the ubiquitous second messenger cAMP. Mammals possess nine isoforms of transmembrane ACs, dubbed AC1-9, that serve as major effector enzymes of G protein-coupled receptors. The transmembrane ACs display varying expression patterns across tissues, giving potential for them having a wide array of physiologic roles. Cells express multiple AC isoforms, implying that ACs have redundant functions. Furthermore, all transmembrane ACs are activated by Gαs so it was long assumed that all ACs are activated by Gαs-coupled GPCRs. AC isoforms partition to different microdomains of the plasma membrane and form prearranged signaling complexes with specific GPCRs that contribute to cAMP signaling compartments. This compartmentation allows for a diversity of cellular and physiological responses by enabling unique signaling events to be triggered by different pools of cAMP. Isoform specific pharmacological activators or inhibitors are lacking for most ACs, making knockdown and overexpression the primary tools for examining the physiological roles of a given isoform. Much progress has been made in understanding the physiological effects mediated through individual transmembrane ACs. GPCR-AC-cAMP signaling pathways play significant roles in regulating functions of every cell and tissue, so understanding each AC isoform's role holds potential for uncovering new approaches for treating a vast array of pathophysiological conditions.


Author(s):  
Lucia Del Valle Anton ◽  
Victor Borrell

The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function and frequently altered in pathological dysfunction. Cortex folding is not unique to humans, nor even to primates, but is common across mammals. Cortical growth and folding are the result of complex developmental processes that involve neural stem and progenitor cells and their cellular lineages, the migration and differentiation of neurons, and the genetic programs that regulate and fine-tune these processes. All these factors combined generate mechanical stress and strain on the developing neural tissue, which ultimately drives orderly cortical deformation and folding. In this review we examine and summarize the current knowledge on the molecular, cellular, histogenic and mechanical mechanisms that are involved in and influence folding of the cerebral cortex, and how they emerged and changed during mammalian evolution. We discuss the main types of pathological malformations of human cortex folding, their specific developmental origin, and how investigating their genetic causes has illuminated our understanding of key events involved. We close our review by presenting the state-of-the-art animal and in vitro models of cortex folding that are currently used to study these devastating developmental brain disorders in children, and what are the main challenges that remain ahead of us to fully understand brain folding.


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