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J Biochem,
2009]
The accumulation of unfolded proteins in the endoplasmic reticulum (ER) under ER stress conditions activates a series of homoeostatic responses collectively termed the unfolded protein response (UPR). The UPR is unique in which the molecular mechanisms it uses to transmit signals from the ER lumen to the nucleus are completely different to those used for signalling from the plasma membrane. An ER stress signal is sensed and transmitted across the membrane by a transmembrane protein(s) in the ER. Interestingly, the number of such functional sensors/transducers, ubiquitously expressed, has increased with evolution, for example, one in Saccharomyces cerevisiae, two in Caenorhabditis elegans and Drosophila melanogaster, and three in mammals. Accordingly, mammalian cells are able to cope with ER stress in a more sophisticated manner. Here, I summarize the mechanisms and activation consequences of UPR signalling pathways in yeast, worm, fly and mammalian cells. I also discuss how they have evolved to counteract ER stress effectively.
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Traffic,
2003]
Proteins must be correctly folded and assembled to fulfill their functions as assigned by genetic code. All living cells have developed systems to counteract protein unfolding or misfolding. A typical example of such a homeostatic response is triggered when unfolded proteins are accumulated in the endoplasmic reticulum. Eukaryotic cells cope with endoplasmic reticulum stress by attenuating translation, generally to decrease the burden on the folding machinery, as well as by inducing transcription of endoplasmic reticulum-localized molecular chaperones and folding enzymes to augment folding capacity. These translational and transcriptional controls are collectively termed the unfolded protein response. The unfolded protein response is unique in that the molecular mechanisms it uses to transmit signals from the endoplasmic reticulum lumen to the nucleus are completely different from those used for signaling from the plasma membrane. Frame switch splicing (a term newly proposed here) and regulated intramembrane proteolysis (proposed by Brown et al., Cell 2000; 100: 391-398) employed by the unfolded protein response represent novel ways to activate a signaling molecule post-transcriptionally and post-translationally, respectively. They are critically involved in various cellular regulation pathways ranging from bacterial extracytoplasmic stress response to differentiation of mature B cells into antibody-secreting plasma cells. Further, mammalian cells take advantage of differential properties between the two mechanisms to determine the fate of proteins unfolded or misfolded in the endoplasmic reticulum. This review focuses on the transcriptional control that occurs during the unfolded protein response in various species.
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Trends Cell Biol,
2010]
A wealth of evidence underscores the tight link between oxidative stress, neurodegeneration and aging. When the level of excess reactive oxygen species (ROS) increases in the cell, a phenomenon characteristic of aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. Recently we showed that in the nematode, Caenorhabditis elegans, oxidation of K(+) channels by ROS is a major mechanism underlying the loss of neuronal function. The C. elegans results support an argument that K(+) channels controlling neuronal excitability and survival might provide a common, functionally important substrate for ROS in aging mammals. Here we discuss the implications that oxidation of K(+) channels by ROS might have for the mammalian brain during normal aging, as well as in neurodegenerative diseases such as Alzheimer's and Parkinson's. We argue that oxidation of K(+) channels by ROS is a common theme in the aging brain and suggest directions for future experimentation.
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Physiology (Bethesda),
2009]
Recent work shows that transport-independent as well as transport-dependent functions of ion transporters, and in particular the Na-K-ATPase, are required for formation and maintenance of several intercellular junctions. Furthermore, these junctional and other nonjunctional functions of ion transporters contribute to development of epithelial tubes. Here, we consider what has been learned about the roles of ion pumps in formation of junctions and epithelial tubes in mammals, zebrafish, Drosophila, and C. elegans. We propose that asymmetric association of the Na-K-ATPase with cell junctions early in metazoan evolution enabled vectorial transcellular ion transport and control of intraorganismal environment. Ion transport-independent functions of the Na-K-ATPase arose as junctional complexes evolved.
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Trends in Pharmacological Sciences,
2005]
K+ channels that possess two pore domains in each channel subunit are common in many animal tissues. Such channels are generated from large families of subunits and are implicated in several functions, including temperature sensation, responses to ischaemia, K+ homeostasis and setting the resting potential of the cell. Their activity can be modulated by polyunsaturated fatty acids, pH and oxygen, and some are candidate targets of volatile anaesthetics. However, despite their potential as targets for novel drugs for human health, comparatively little is known about the molecular basis of their diverse physiological and pharmacological properties. Genetic model organisms have considerable potential for improving our understanding of these channels. In this article, we review the contributions of some of these genetic model organisms to recent advances in our knowledge of two-pore-domain K+
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Mech Ageing Dev,
2018]
Past investigations have shown that various plant extracts are capable of promoting longevity in lower model organisms like Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, Bombyx mori etc. Longevity studies on such organisms provide a foundation to explore anti-aging efficacies of such plant extracts in higher organisms. Plant extracts of acai palm, apple, asparagus, blueberry, cinnamon, cocoa, Damnacanthus, maize, mistletoe, peach, pomegranate, Rhodiola, rose, Sasa, turmeric, and Withania have extended lifespan in lower model organisms via diverse mechanisms like insulin like growth factor (IGF) signaling pathway, and antioxidant defense mechanisms. Knowledge of pathways altered by the extracts can be investigated as potential drug-targets for natural anti-aging interventions. Thus, the aim of the review is to scrutinize longevity promoting efficacies of various plant extracts in lower model organisms.
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Nature Cell Biology,
1999]
Studies on the role of cholesterol- and caveolin-rich membrane microdomains in localizing Ras to the plasma membrane and enabling its signalling activity reveal intriguing differences both between mammalian H-Ras and K-Ras and between requirements for Ras signalling in mammalian and nematode cells.
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Biochim Biophys Acta,
2010]
Precise regulation of the intracellular concentration of chloride [Cl-]i is necessary for proper cell volume regulation, transepithelial transport, and GABA neurotransmission. The Na-K-2Cl (NKCCs) and K-Cl (KCCs) cotransporters, related SLC12A transporters mediating cellular chloride influx and efflux, respectively, are key determinants of [Cl-]i in numerous cell types, including red blood cells, epithelial cells, and neurons. A common "chloride/volume-sensitive kinase", or related system of kinases, has long been hypothesized to mediate the reciprocal but coordinated phosphoregulation of the NKCCs and the KCCs, but the identity of these kinase(s) has remained unknown. Recent evidence suggests that the WNK (with no lysine = K) serine-threonine kinases directly or indirectly via the downstream Ste20-type kinases SPAK/OSR1, are critical components of this signaling pathway. Hypertonic stress (cell shrinkage), and possibly decreased [Cl-]i, triggers the phosphorylation and activation of specific WNKs, promoting NKCC activation and KCC inhibition via net transporter phosphorylation. Silencing WNK kinase activity can promote NKCC inhibition and KCC activation via net transporter dephosphorylation, revealing a dynamic ability of the WNKs to modulate [Cl-]. This pathway is essential for the defense of cell volume during osmotic perturbation, coordination of epithelial transport, and gating of sensory information in the peripheral system. Commiserate with their importance in serving these critical roles in humans, mutations in WNKs underlie two different Mendelian diseases, pseudohypoaldosteronism type II (an inherited form of salt-sensitive hypertension), and hereditary sensory and autonomic neuropathy type 2. WNKs also regulate ion transport in lower multicellular organisms, including Caenorhabditis elegans, suggesting that their functions are evolutionarily-conserved. An increased understanding of how the WNKs regulate the Na-K-2Cl and K-Cl cotransporters may provide novel opportunities for the selective modulation of these transporters, with ramifications for common human diseases like hypertension, sickle cell disease, neuropathic pain, and epilepsy.
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FEMS Immunol Med Microbiol,
2005]
Recently, the use of invertebrate models of infection has given exciting insights into host-pathogen interaction for a number of bacteria. In particular, this has revealed important factors of the host response with remarkable parallels in higher organisms. Here, we review the advances attained in the elucidation of virulence determinants of a major human pathogen, Staphylococcus aureus, in relation to the invertebrate models thus far applied, the silkworm (Bombyx mori), the fruit fly (Drosophila melanogaster) and the roundworm (Caenorhabditis elegans). Also, the major pathways of host defence are covered in light of the response to S. aureus and the similarities and divergences in innate immunity of vertebrates and invertebrates. Consequently, we comparatively consider pathogen recognition receptors, signal transduction pathways (including Toll, Imd and others), and the humoral and cellular antimicrobial effectors. The technically convenient and ethically acceptable invertebrates appear as a valuable first tool to discriminate molecules participating from both sides of the host-S. aureus interaction as well as a high throughput method for antimicrobial screening.
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Aging Dis,
2016]
Reversible regulation of proteins by reactive oxygen species (ROS) is an important mechanism of neuronal plasticity. In particular, ROS have been shown to act as modulatory molecules of ion channels-which are key to neuronal excitability-in several physiological processes. However ROS are also fundamental contributors to aging vulnerability. When the level of excess ROS increases in the cell during aging, DNA is damaged, proteins are oxidized, lipids are degraded and more ROS are produced, all culminating in significant cell injury. From this arose the idea that oxidation of ion channels by ROS is one of the culprits for neuronal aging. Aging-dependent oxidative modification of voltage-gated potassium (K(+)) channels was initially demonstrated in the nematode Caenorhabditis elegans and more recently in the mammalian brain. Specifically, oxidation of the delayed rectifier KCNB1 (Kv2.1) and of Ca(2+)- and voltage sensitive K(+) channels have been established suggesting that their redox sensitivity contributes to altered excitability, progression of healthy aging and of neurodegenerative disease. Here I discuss the implications that oxidation of K(+) channels by ROS may have for normal aging, as well as for neurodegenerative disease.