Sesti F et al. (2010) Trends Cell Biol "Oxidation of potassium channels by ROS: a general mechanism of aging and neurodegeneration?"

Cai SQ, Liu S, Sesti F

[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.

Krupinski T et al. (2009) Physiology (Bethesda) "Unexpected roles of the Na-K-ATPase and other ion transporters in cell junctions and tubulogenesis."

Beitel GJ, Krupinski T

[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.

Buckingham, SD et al. (2005) Trends in Pharmacological Sciences "Structure and function of two-pore-domain K+ channels: contributions from genetic model organisms."

Franks, CJ, Buckingham, SD, Law, RJ, Sattelle, DB, Kidd, JF

[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+

Sternberg PW et al. (1999) Nature Cell Biology "Caveolin, cholesterol and Ras signalling."

Schmid SL, Sternberg PW

[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.

Kahle KT et al. (2010) Biochim Biophys Acta "Phosphoregulation of the Na-K-2Cl and K-Cl cotransporters by the WNK kinases."

Lifton RP, Kahle KT, Rinehart J

[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.

Sesti F (2016) Aging Dis "Oxidation of K(+) Channels in Aging and Neurodegeneration."

Sesti F

[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.

Blaustein MP et al. (1999) Physiol Rev "Sodium/calcium exchange: its physiological implications."

Blaustein MP, Lederer WJ

[Physiol Rev, 1999]

The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

Folgering JH et al. (2008) Prog Biophys Mol Biol "Molecular basis of the mammalian pressure-sensitive ion channels: focus on vascular mechanotransduction."

Dedman A, Patel A, Delmas P, Honore E, Folgering JH, Sharif-Naeini R

[Prog Biophys Mol Biol, 2008]

Mechano-gated ion channels are implicated in a variety of neurosensory functions ranging from touch sensitivity to hearing. In the heart, rhythm disturbance subsequent to mechanical effects is also associated with the activation of stretch-sensitive ion channels. Arterial autoregulation in response to hemodynamic stimuli, a vital process required for protection against hypertension-induced injury, is similarly dependent on the activity of force-sensitive ion channels. Seminal work in prokaryotes and invertebrates, including the nematode Caenorhabditis elegans and the fruit fly drosophila, greatly helped to identify the molecular basis of volume regulation, hearing and touch sensitivity. In mammals, more recent findings have indicated that members of several structural family of ion channels, namely the transient receptor potential (TRP) channels, the amiloride-sensitive ENaC/ASIC channels and the potassium channels K(2P) and K(ir) are involved in cellular mechanotransduction. In the present review, we will focus on the molecular and functional properties of these channel subunits and will emphasize on their role in the pressure-dependent arterial myogenic constriction and the flow-mediated vasodilation.

Chatterjee N et al. (2008) Prog Brain Res "Understanding the mind of a worm: hierarchical network structure underlying nervous system function in C. elegans."

Sinha S, Chatterjee N

[Prog Brain Res, 2008]

The nervous system of the nematode C. elegans provides a unique opportunity to understand how behavior (''mind'') emerges from activity in the nervous system (''brain'') of an organism. The hermaphrodite worm has only 302 neurons, all of whose connections (synaptic and gap junctional) are known. Recently, many of the functional circuits that make up its behavioral repertoire have begun to be identified. In this paper, we investigate the hierarchical structure of the nervous system through k-core decomposition and find it to be intimately related to the set of all known functional circuits. Our analysis also suggests a vital role for the lateral ganglion in processing information, providing an essential connection between the sensory and motor components of the C. elegans nervous system.

Ehrhardt A et al. (2002) Exp Hematol "Ras and relatives--job sharing and networking keep an old family together."

Guo X, Ehrhardt A, Schrader JW, Ehrhardt GR

[Exp Hematol, 2002]

Many members of the Ras superfamily of GTPases have been implicated in the regulation of hematopoietic cells, with roles in growth, survival, differentiation, cytokine production, chemotaxis, vesicle-trafficking, and phagocytosis. The well-known p21 Ras proteins H-Ras, N-Ras, K-Ras 4A, and K-Ras 4B are also frequently mutated in human cancer and leukemia. Besides the four p21 Ras proteins, the Ras subfamily of the Ras superfamily includes R-Ras, TC21 (R-Ras2), M-Ras (R-Ras3), Rap1A, Rap1B, Rap2A, Rap2B, RalA, and RalB. They exhibit remarkable overall amino acid identities, especially in the regions interacting with the guanine nucleotide exchange factors that catalyze their activation. In addition, there is considerable sharing of various downstream effectors through which they transmit signals and of GTPase activating proteins that downregulate their activity, resulting in overlap in their regulation and effector function. Relatively little is known about the physiological functions of individual Ras family members, although the presence of well-conserved orthologs in Caenorhabditis elegans suggests that their individual roles are both specific and vital. The structural and functional similarities have meant that commonly used research tools fail to discriminate between the different family members, and functions previously attributed to one family member may be shared with other members of the Ras family. Here we discuss similarities and differences in activation, effector usage, and functions of different members of the Ras subfamily. We also review the possibility that the differential localization of Ras proteins in different parts of the cell membrane may govern their responses to activation of cell surface receptors.