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1.
Annu Rev Biochem ; 90: 559-579, 2021 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-33492991

RESUMEN

Microorganisms contend with numerous and unusual chemical threats and have evolved a catalog of resistance mechanisms in response. One particularly ancient, pernicious threat is posed by fluoride ion (F-), a common xenobiotic in natural environments that causes broad-spectrum harm to metabolic pathways. This review focuses on advances in the last ten years toward understanding the microbial response to cytoplasmic accumulation of F-, with a special emphasis on the structure and mechanisms of the proteins that microbes use to export fluoride: the CLCF family of F-/H+ antiporters and the Fluc/FEX family of F- channels.


Asunto(s)
Antiportadores/química , Antiportadores/metabolismo , Fluoruros/metabolismo , Canales Iónicos/química , Canales Iónicos/metabolismo , Canales de Cloruro/química , Canales de Cloruro/metabolismo , Citoplasma/metabolismo , Fluoruros/toxicidad , Transporte Iónico , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Conformación Proteica , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo
2.
Annu Rev Biochem ; 89: 583-603, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-31874046

RESUMEN

P-type ATPases are found in all kingdoms of life and constitute a wide range of cation transporters, primarily for H+, Na+, K+, Ca2+, and transition metal ions such as Cu(I), Zn(II), and Cd(II). They have been studied through a wide range of techniques, and research has gained very significant insight on their transport mechanism and regulation. Here, we review the structure, function, and dynamics of P2-ATPases including Ca2+-ATPases and Na,K-ATPase. We highlight mechanisms of functional transitions that are associated with ion exchange on either side of the membrane and how the functional cycle is regulated by interaction partners, autoregulatory domains, and off-cycle states. Finally, we discuss future perspectives based on emerging techniques and insights.


Asunto(s)
Adenosina Trifosfato/química , ATPasas Transportadoras de Cobre/química , ATPasa Intercambiadora de Hidrógeno-Potásio/química , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/química , ATPasa Intercambiadora de Sodio-Potasio/química , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión , Cationes Bivalentes , Cationes Monovalentes , ATPasas Transportadoras de Cobre/genética , ATPasas Transportadoras de Cobre/metabolismo , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Transporte Iónico , Modelos Moleculares , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Protones , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Imagen Individual de Molécula , ATPasa Intercambiadora de Sodio-Potasio/genética , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Especificidad por Sustrato
3.
Annu Rev Biochem ; 88: 59-83, 2019 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-30830799

RESUMEN

Directional transport of protons across an energy transducing membrane-proton pumping-is ubiquitous in biology. Bacteriorhodopsin (bR) is a light-driven proton pump that is activated by a buried all-trans retinal chromophore being photoisomerized to a 13-cis conformation. The mechanism by which photoisomerization initiates directional proton transport against a proton concentration gradient has been studied by a myriad of biochemical, biophysical, and structural techniques. X-ray free electron lasers (XFELs) have created new opportunities to probe the structural dynamics of bR at room temperature on timescales from femtoseconds to milliseconds using time-resolved serial femtosecond crystallography (TR-SFX). Wereview these recent developments and highlight where XFEL studies reveal new details concerning the structural mechanism of retinal photoisomerization and proton pumping. We also discuss the extent to which these insights were anticipated by earlier intermediate trapping studies using synchrotron radiation. TR-SFX will open up the field for dynamical studies of other proteins that are not naturally light-sensitive.


Asunto(s)
Bacteriorodopsinas/ultraestructura , Rayos Láser , Protones , Retinaldehído/química , Difracción de Rayos X/métodos , Bacteriorodopsinas/química , Bacteriorodopsinas/metabolismo , Cristalografía/instrumentación , Cristalografía/métodos , Halobacterium salinarum/química , Halobacterium salinarum/metabolismo , Transporte Iónico , Modelos Moleculares , Conformación Proteica , Retinaldehído/metabolismo , Sincrotrones/instrumentación , Rayos X
4.
Cell ; 175(3): 890-890.e1, 2018 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-30340048

RESUMEN

Genetic ataxias are a clinically important group of disabling, mostly neurodegenerative, diseases of the cerebellum. This SnapShot shows that the vast majority of established monogenic causes of dominant and recessive ataxias can be captured by a limited number of affected cellular components and biological processes in the cerebellum. To view this SnapShot, open or download the PDF.


Asunto(s)
Ataxia Cerebelosa/genética , Animales , Ataxia Cerebelosa/metabolismo , Reparación del ADN , Humanos , Transporte Iónico , Células de Purkinje/metabolismo
5.
Annu Rev Biochem ; 85: 161-92, 2016 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-27145841

RESUMEN

In the last 5 years, most of the molecules that control mitochondrial Ca(2+) homeostasis have been finally identified. Mitochondrial Ca(2+) uptake is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, a macromolecular structure that guarantees Ca(2+) accumulation inside mitochondrial matrix upon increases in cytosolic Ca(2+). Conversely, Ca(2+) release is under the control of the Na(+)/Ca(2+) exchanger, encoded by the NCLX gene, and of a H(+)/Ca(2+) antiporter, whose identity is still debated. The low affinity of the MCU complex, coupled to the activity of the efflux systems, protects cells from continuous futile cycles of Ca(2+) across the inner mitochondrial membrane and consequent massive energy dissipation. In this review, we discuss the basic principles that govern mitochondrial Ca(2+) homeostasis and the methods used to investigate the dynamics of Ca(2+) concentration within the organelles. We discuss the functional and structural role of the different molecules involved in mitochondrial Ca(2+) handling and their pathophysiological role.


Asunto(s)
Canales de Calcio/metabolismo , Calcio/metabolismo , Mitocondrias/metabolismo , Intercambiador de Sodio-Calcio/metabolismo , Animales , Canales de Calcio/química , Canales de Calcio/genética , Señalización del Calcio , Regulación de la Expresión Génica , Homeostasis , Humanos , Transporte Iónico , Cinética , Mitocondrias/genética , Mitocondrias/ultraestructura , Membranas Mitocondriales/metabolismo , Membranas Mitocondriales/ultraestructura , Proteínas Mitocondriales , Modelos Moleculares , Intercambiador de Sodio-Calcio/genética , Termodinámica
6.
Nature ; 626(8001): 963-974, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38418916

RESUMEN

Transporting small molecules across cell membranes is an essential process in cell physiology. Many structurally diverse, secondary active transporters harness transmembrane electrochemical gradients of ions to power the uptake or efflux of nutrients, signalling molecules, drugs and other ions across cell membranes. Transporters reside in lipid bilayers on the interface between two aqueous compartments, where they are energized and regulated by symported, antiported and allosteric ions on both sides of the membrane and the membrane bilayer itself. Here we outline the mechanisms by which transporters couple ion and solute fluxes and discuss how structural and mechanistic variations enable them to meet specific physiological needs and adapt to environmental conditions. We then consider how general bilayer properties and specific lipid binding modulate transporter activity. Together, ion gradients and lipid properties ensure the effective transport, regulation and distribution of small molecules across cell membranes.


Asunto(s)
Transporte Biológico Activo , Iones , Membrana Dobles de Lípidos , Lípidos , Proteínas de Transporte de Membrana , Transporte Iónico , Iones/metabolismo , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/metabolismo
7.
Nature ; 633(8031): 872-877, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39198644

RESUMEN

Early plant responses to different stress situations often encompass cytosolic Ca2+ increases, plasma membrane depolarization and the generation of reactive oxygen species1-3. However, the mechanisms by which these signalling elements are translated into defined physiological outcomes are poorly understood. Here, to study the basis for encoding of specificity in plant signal processing, we used light-gated ion channels (channelrhodopsins). We developed a genetically engineered channelrhodopsin variant called XXM 2.0 with high Ca2+ conductance that enabled triggering cytosolic Ca2+ elevations in planta. Plant responses to light-induced Ca2+ influx through XXM 2.0 were studied side by side with effects caused by an anion efflux through the light-gated anion channelrhodopsin ACR1 2.04. Although both tools triggered membrane depolarizations, their activation led to distinct plant stress responses: XXM 2.0-induced Ca2+ signals stimulated production of reactive oxygen species and defence mechanisms; ACR1 2.0-mediated anion efflux triggered drought stress responses. Our findings imply that discrete Ca2+ signals and anion efflux serve as triggers for specific metabolic and transcriptional reprogramming enabling plants to adapt to particular stress situations. Our optogenetics approach unveiled that within plant leaves, distinct physiological responses are triggered by specific ion fluxes, which are accompanied by similar electrical signals.


Asunto(s)
Arabidopsis , Señalización del Calcio , Calcio , Channelrhodopsins , Luz , Optogenética , Aniones/metabolismo , Arabidopsis/citología , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/efectos de la radiación , Calcio/metabolismo , Señalización del Calcio/efectos de la radiación , Membrana Celular/metabolismo , Membrana Celular/efectos de la radiación , Channelrhodopsins/metabolismo , Channelrhodopsins/genética , Citosol/metabolismo , Sequías , Conductividad Eléctrica , Transporte Iónico/efectos de la radiación , Hojas de la Planta/genética , Hojas de la Planta/metabolismo , Hojas de la Planta/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Estrés Fisiológico/genética , Estrés Fisiológico/efectos de la radiación , Regulación de la Expresión Génica de las Plantas/efectos de la radiación
8.
EMBO J ; 43(2): 196-224, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38177502

RESUMEN

Ion channels, transporters, and other ion-flux controlling proteins, collectively comprising the "ion permeome", are common drug targets, however, their roles in cancer remain understudied. Our integrative pan-cancer transcriptome analysis shows that genes encoding the ion permeome are significantly more often highly expressed in specific subsets of cancer samples, compared to pan-transcriptome expectations. To enable target selection, we identified 410 survival-associated IP genes in 33 cancer types using a machine-learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and are associated with poor prognosis in glioblastoma, the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived glioblastoma cells induces transcriptome-wide changes involving neuron projection and proliferation pathways, impairs cell viability and tumor sphere formation in vitro, perturbs tunneling nanotube dynamics, and extends the survival of glioblastoma-bearing mice. Thus, aberrant activation of genes encoding ion transport proteins appears as a pan-cancer feature defining tumor heterogeneity, which can be exploited for mechanistic insights and therapy development.


Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Animales , Ratones , Glioblastoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Transcriptoma , Transporte Iónico/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Canal de Sodio Activado por Voltaje NAV1.7/genética
9.
Nat Immunol ; 17(9): 1075-83, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27400149

RESUMEN

Adhesion and migration of T cells are controlled by chemokines and by adhesion molecules, especially integrins, and have critical roles in the normal physiological function of T lymphocytes. Using an RNA-mediated interference screen, we identified the WNK1 kinase as a regulator of both integrin-mediated adhesion and T cell migration. We found that WNK1 is a negative regulator of integrin-mediated adhesion, whereas it acts as a positive regulator of migration via the kinases OXSR1 and STK39 and the ion co-transporter SLC12A2. WNK1-deficient T cells home less efficiently to lymphoid organs and migrate more slowly through them. Our results reveal that a pathway previously known only to regulate salt homeostasis in the kidney functions to balance T cell adhesion and migration.


Asunto(s)
Adhesión Celular/genética , Movimiento Celular/genética , Antígenos de Histocompatibilidad Menor/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores Mensajeros de Linfocitos/metabolismo , Linfocitos T/fisiología , Animales , Células Cultivadas , Homeostasis , Transporte Iónico , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/genética , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , Receptores Mensajeros de Linfocitos/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Proteína Quinasa Deficiente en Lisina WNK 1
10.
Nat Rev Mol Cell Biol ; 17(5): 293-307, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-27033257

RESUMEN

Cells need to regulate their volume to counteract osmotic swelling or shrinkage, as well as during cell division, growth, migration and cell death. Mammalian cells adjust their volume by transporting potassium, sodium, chloride and small organic osmolytes using plasma membrane channels and transporters. This generates osmotic gradients, which drive water in and out of cells. Key players in this process are volume-regulated anion channels (VRACs), the composition of which has recently been identified and shown to encompass LRRC8 heteromers. VRACs also transport metabolites and drugs and function in extracellular signal transduction, apoptosis and anticancer drug resistance.


Asunto(s)
Tamaño de la Célula , Canales Aniónicos Dependientes del Voltaje/fisiología , Animales , Apoptosis , Membrana Celular , Permeabilidad de la Membrana Celular , Humanos , Transporte Iónico , Potenciales de la Membrana , Transducción de Señal
11.
Nature ; 612(7941): 795-801, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36517601

RESUMEN

The sodium/iodide symporter (NIS) is the essential plasma membrane protein that mediates active iodide (I-) transport into the thyroid gland, the first step in the biosynthesis of the thyroid hormones-the master regulators of intermediary metabolism. NIS couples the inward translocation of I- against its electrochemical gradient to the inward transport of Na+ down its electrochemical gradient1,2. For nearly 50 years before its molecular identification3, NIS was the molecule at the centre of the single most effective internal radiation cancer therapy: radioiodide (131I-) treatment for thyroid cancer2. Mutations in NIS cause congenital hypothyroidism, which must be treated immediately after birth to prevent stunted growth and cognitive deficiency2. Here we report three structures of rat NIS, determined by single-particle cryo-electron microscopy: one with no substrates bound; one with two Na+ and one I- bound; and one with one Na+ and the oxyanion perrhenate bound. Structural analyses, functional characterization and computational studies show the substrate-binding sites and key residues for transport activity. Our results yield insights into how NIS selects, couples and translocates anions-thereby establishing a framework for understanding NIS function-and how it transports different substrates with different stoichiometries and releases substrates from its substrate-binding cavity into the cytosol.


Asunto(s)
Yoduros , Sodio , Simportadores , Animales , Ratas , Microscopía por Crioelectrón , Yoduros/metabolismo , Sodio/metabolismo , Simportadores/química , Simportadores/metabolismo , Simportadores/ultraestructura , Sitios de Unión , Especificidad por Sustrato , Transporte Iónico
12.
Annu Rev Cell Dev Biol ; 30: 439-63, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25288116

RESUMEN

Astrocytes regulate multiple aspects of neuronal and synaptic function from development through to adulthood. Instead of addressing each function independently, this review provides a comprehensive overview of the different ways astrocytes modulate neuronal synaptic function throughout life, with a particular focus on recent findings in each area. It includes the emerging functions of astrocytes, such as a role in synapse formation, as well as more established roles, including the uptake and recycling of neurotransmitters. This broad approach covers the many ways astrocytes and neurons constantly interact to maintain the correct functioning of the brain. It is important to consider all of these diverse functions of astrocytes when investigating how astrocyte-neuron interactions regulate synaptic behavior to appreciate the complexity of these ongoing interactions.


Asunto(s)
Astrocitos/fisiología , Proteínas del Tejido Nervioso/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Animales , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Señalización del Calcio , Comunicación Celular , Ácido Glutámico/fisiología , Humanos , Transporte Iónico , Lípidos/biosíntesis , Neuronas/fisiología , Neurotransmisores/fisiología , Proteínas de Transporte de Neurotransmisores/fisiología , Potasio/metabolismo , Receptores de Neurotransmisores/fisiología
13.
Annu Rev Cell Dev Biol ; 30: 317-36, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25062359

RESUMEN

Localized ion fluxes at the plasma membrane provide electrochemical gradients at the cell surface that contribute to cell polarization, migration, and division. Ion transporters, local pH gradients, membrane potential, and organization are emerging as important factors in cell polarization mechanisms. The power of electrochemical effects is illustrated by the ability of exogenous electric fields to redirect polarization in cells ranging from bacteria, fungi, and amoebas to keratocytes and neurons. Electric fields normally surround cells and tissues and thus have been proposed to guide cell polarity in development, cancer, and wound healing. Recent studies on electric field responses in model systems and development of new biosensors provide new avenues to dissect molecular mechanisms. Here, we review recent advances that bring molecular understanding of how electrochemistry contributes to cell polarity in various contexts.


Asunto(s)
Polaridad Celular/fisiología , Animales , Aniones/metabolismo , Cationes/metabolismo , División Celular , Movimiento Celular , Forma de la Célula , Dictyostelium/citología , Electroquímica , Campos Electromagnéticos , Peces , Hongos/citología , Concentración de Iones de Hidrógeno , Líquido Intracelular/química , Transporte Iónico/fisiología , Potenciales de la Membrana/fisiología , Regeneración , Electricidad Estática , Cicatrización de Heridas
14.
EMBO J ; 42(13): e112198, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37278161

RESUMEN

There is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller.


Asunto(s)
Neoplasias de la Próstata , Sodio , Masculino , Humanos , Sodio/metabolismo , Canales Iónicos/metabolismo , Transporte Iónico , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo
15.
PLoS Biol ; 22(8): e3002719, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39167625

RESUMEN

The band 3 transporter is a critical integral membrane protein of the red blood cell (RBC), as it is responsible for catalyzing the exchange of bicarbonate and chloride anions across the plasma membrane. To elucidate the structural mechanism of the band 3 transporter, detergent solubilized human ghost membrane reconstituted in nanodiscs was applied to a cryo-EM holey carbon grid to define its composition. With this approach, we identified and determined structural information of the human band 3 transporter. Here, we present 5 different cryo-EM structures of the transmembrane domain of dimeric band 3, either alone or bound with chloride or bicarbonate. Interestingly, we observed that human band 3 can form both symmetric and asymmetric dimers with a different combination of outward-facing (OF) and inward-facing (IF) states. These structures also allow us to obtain the first model of a human band 3 molecule at the IF conformation. Based on the structural data of these dimers, we propose a model of ion transport that is in favor of the elevator-type mechanism.


Asunto(s)
Proteína 1 de Intercambio de Anión de Eritrocito , Bicarbonatos , Cloruros , Microscopía por Crioelectrón , Humanos , Microscopía por Crioelectrón/métodos , Bicarbonatos/metabolismo , Cloruros/metabolismo , Proteína 1 de Intercambio de Anión de Eritrocito/metabolismo , Proteína 1 de Intercambio de Anión de Eritrocito/química , Transporte Iónico , Modelos Moleculares , Multimerización de Proteína , Conformación Proteica , Membrana Celular/metabolismo
16.
Proc Natl Acad Sci U S A ; 121(16): e2320416121, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38588428

RESUMEN

Pores through ion channels rapidly transport small inorganic ions along their electrochemical gradients. Here, applying single-channel electrophysiology and mutagenesis to the archetypal muscle nicotinic acetylcholine receptor (AChR) channel, we show that a conserved pore-peripheral salt bridge partners with those in the other subunits to regulate ion transport. Disrupting the salt bridges in all five receptor subunits greatly decreases the amplitude of the unitary current and increases its fluctuations. However, disrupting individual salt bridges has unequal effects that depend on the structural status of the other salt bridges. The AChR ε- and δ-subunits are structurally unique in harboring a putative palmitoylation site near each salt bridge and bordering the lipid membrane. The effects of disrupting the palmitoylation sites mirror those of disrupting the salt bridges, but the effect of disrupting either of these structures depends on the structural status of the other. Thus, rapid ion transport through the AChR channel is maintained by functionally interdependent salt bridges linking the pore to the lipid membrane.


Asunto(s)
Receptores Colinérgicos , Receptores Nicotínicos , Receptores Nicotínicos/genética , Receptores Nicotínicos/química , Músculos , Transporte Iónico , Lípidos
17.
Proc Natl Acad Sci U S A ; 121(9): e2316673121, 2024 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-38381791

RESUMEN

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that regulates transepithelial salt and fluid homeostasis. CFTR dysfunction leads to reduced chloride secretion into the mucosal lining of epithelial tissues, thereby causing the inherited disease cystic fibrosis. Although several structures of CFTR are available, our understanding of the ion-conduction pathway is incomplete. In particular, the route that connects the cytosolic vestibule with the extracellular space has not been clearly defined, and the structure of the open pore remains elusive. Furthermore, although many residues have been implicated in altering the selectivity of CFTR, the structure of the "selectivity filter" has yet to be determined. In this study, we identify a chloride-binding site at the extracellular ends of transmembrane helices 1, 6, and 8, where a dehydrated chloride is coordinated by residues G103, R334, F337, T338, and Y914. Alterations to this site, consistent with its function as a selectivity filter, affect ion selectivity, conductance, and open channel block. This selectivity filter is accessible from the cytosol through a large inner vestibule and opens to the extracellular solvent through a narrow portal. The identification of a chloride-binding site at the intra- and extracellular bridging point leads us to propose a complete conductance path that permits dehydrated chloride ions to traverse the lipid bilayer.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Humanos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Cloruros/metabolismo , Fibrosis Quística/genética , Transporte Iónico , Estructura Secundaria de Proteína
18.
Proc Natl Acad Sci U S A ; 121(33): e2403903121, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39116127

RESUMEN

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.


Asunto(s)
Conexinas , Humanos , Conexinas/metabolismo , Conexinas/genética , Transporte Iónico , Animales , Mutación , Iones/metabolismo , Uniones Comunicantes/metabolismo , Canales Iónicos/metabolismo , Canales Iónicos/genética
19.
Trends Biochem Sci ; 47(10): 822-823, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35597714

RESUMEN

Mous et al. recently reported the molecular mechanism of chloride transport through a light-activated pumping rhodopsin, a key process involved in a range of cellular functions. Their results open exciting new challenges for photopharmacology and computational modeling that should be addressed in the coming years.


Asunto(s)
Luz , Rodopsina , Simulación por Computador , Transporte Iónico
20.
Physiol Rev ; 99(1): 235-309, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-30354966

RESUMEN

The thick ascending limb plays a key role in maintaining water and electrolyte balance. The importance of this segment in regulating blood pressure is evidenced by the effect of loop diuretics or local genetic defects on this parameter. Hormones and factors produced by thick ascending limbs have both autocrine and paracrine effects, which can extend prohypertensive signaling to other structures of the nephron. In this review, we discuss the role of the thick ascending limb in the development of hypertension, not as a sole participant, but one that works within the rich biological context of the renal medulla. We first provide an overview of the basic physiology of the segment and the anatomical considerations necessary to understand its relationship with other renal structures. We explore the physiopathological changes in thick ascending limbs occurring in both genetic and induced animal models of hypertension. We then discuss the racial differences and genetic defects that affect blood pressure in humans through changes in thick ascending limb transport rates. Throughout the text, we scrutinize methodologies and discuss the limitations of research techniques that, when overlooked, can lead investigators to make erroneous conclusions. Thus, in addition to advancing an understanding of the basic mechanisms of physiology, the ultimate goal of this work is to understand our research tools, to make better use of them, and to contextualize research data. Future advances in renal hypertension research will require not only collection of new experimental data, but also integration of our current knowledge.


Asunto(s)
Presión Sanguínea/fisiología , Extremidades/irrigación sanguínea , Hipertensión/metabolismo , Transporte Iónico/fisiología , Sodio/metabolismo , Animales , Humanos , Equilibrio Hidroelectrolítico/fisiología
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