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PhET: Membrane Channels - Biology
Diffusion is the movement of particles from high concentration to low concentration in a substance. This process is essential for life on Earth, allowing for the movement of molecular compounds into and out of the cell. All matter in the universe is in motion, because all molecules are vibrating. This constant vibration is known as Brownian motion, which can be seen as random zig - zag motion in particles.
PhET Lab experiments represent real interactive, and research-based simulations of physical phenomena from the PhET™ project at the University of Colorado. For teachers and students around the world, the PhET project provides interactive simulations that are based on extensive education research and support more effective science education. Going beyond traditional educational resources, PhET simulations offer an intuitive, game-like environment where students can learn through scientist-like exploration, where dynamic visual representations make the invisible visible, and where science ideas are connected to real-world phenomena. Unlike some educational software, these simulations are free, easily translated into multiple languages, and available either online or offline. PhET simulations are very flexible tools that can be used in many ways. PhET offers tips for integrating these simulations into your class.
All PhET simulations are available for free from the PhET website. They are written in Java and Flash, and can be run using a standard web browser as long as Flash and Java are installed. The PhET project is hard at work increasing the accessibility of their simulations, and a number of PhET simulations have accessibility features.
There are 19 simulations in the PhET Biology Collection. Here are some highlights:
Function and structure
The flow of charged ions through open channels represents an electrical current that changes the voltage across the membrane by altering the distribution of charge. In excitable cells, voltage-gated channels that allow transient influx of positive ions (e.g., sodium and calcium ions) underlie brief depolarizations of the membrane known as action potentials. Action potentials can be transmitted rapidly over long distances, allowing for coordination and precise timing of physiological outputs. In nearly all cases, action potentials trigger downstream physiological effects, such as secretion or muscle contraction, by opening voltage-gated calcium-selective ion channels and elevating intracellular calcium concentration.
The amino acid sequences of many different ion channel proteins have been determined, and in a few cases the X-ray crystal structure of the channel is known as well. Based on their structure, the majority of ion channels can be classified into six or seven superfamilies. For potassium-selective channels, which are among the best-characterized ion channels, four homologous transmembrane subunits come together to create a tunnel, known as the conducting pore, that provides a polar pathway through the nonpolar lipid membrane. Other channel types require either three or five homologous subunits to generate the central conducting pore. In solution, ions are stabilized by polarized water molecules in the surrounding environment. Narrow, highly selective ion channels mimic the water environment by lining the conducting pore with polarized carbonyl oxygen atoms. Less-selective channels form pores with a diameter large enough that ions and water molecules may pass through together.
PhET: Membrane Channels - Biology
At UVA’s Center for Membrane and Cell Physiology, we strive to understand fundamental biological processes at the highest possible spatial and time resolution. Our ultimate goal is to use high-end imaging, structural, biophysical, and biological and chemical probe technologies to make impactful discoveries on understanding the causes, development and cures of diseases ranging from cardiovascular to cancer to neurological and infectious diseases.
Our faculty is comprised of researchers from nine Departments and three Schools at the University of Virginia. They share common research interests and facilities including high-end structural biology and microscopy equipment to achieve a deeper understanding of how cells and in particular cell membranes function.
Meet the Director
Dr. Lukas K. Tamm directs the Center for Membrane and Cell Physiology. His research interests include studies on virus entry into cells by membrane fusion, neurotransmitter release at synapses by exocytosis of synaptic vesicles at nerve termini, and the study of the structures of bacterial outer membrane transporters by nuclear magnetic resonance. Learn More
Research Areas at the Center
Membrane and Cell Physiology faculty focus their research on the following areas: Membrane Transport Membrane Fusion Host-Pathogen Interactions Signal Transduction and Membrane Channels & Receptors. Read about the research areas
Methods and Resources at the Center
Faculty use the following methods and resources for research: Electron Microscopy Magnetic Resonance Spectroscopy Molecular Modeling and Computer Simulation Optical Microscopy and Single Molecule Fluorescence and X-ray Crystallography. Current Resources
The Mitochondrial Calcium Fluxes and Their Regulation in Cell Death
Mitochondrial Calcium Uniporter Complex
Mitochondrial Ca 2+ channels participate in many intracellular signaling pathways both in physiological and in pathological conditions and crucially balance cell life versus death (Giacomello et al., 2007 Duchen et al., 2008). Indeed, as mentioned above, calcium overload in the mitochondria matrix leads to persistent PTP opening and eventually to cell death. Therefore, matrix calcium level has to be highly regulated by modulating the activity of IMM calcium-permeable ion channels and transporters (Rizzuto et al., 2012 Zavodnik, 2016).
Mitochondria can rapidly achieve a high [Ca 2+ ]matrix thanks to the presence of a huge driving force generated by a ΔΨm of mV under physiological conditions, and to the tight contact between the ER and mitochondria that allows direct channeling for Ca 2+ (Rizzuto et al., 1998 Naon and Scorrano, 2014 Giorgi et al., 2015) (see Figure 1).
Calcium entry is primarily mediated by the mitochondrial calcium uniport (MCU) complex (Baughman et al., 2011 De Stefani et al., 2011), which is able to sense the Ca 2+ signals originating from the ER, while release takes place through the Na + /Ca 2+ exchanger NCLX (Palty et al., 2010). At the current stage, the mammalian MCUC appears to consist of at least of the pore-forming protein MCU, a dominant-negative MCU paralog (MCUb), the essential MCU regulator (EMRE), the regulatory MICU proteins (MICU1-3), and possibly, the mitochondrial calcium uniport regulator 1 (MCUR1) (for reviews see e.g., (Marchi and Pinton, 2014 De Stefani et al., 2015 Wagner et al., 2016 Cui et al., 2019). Interestingly, MCU also conducts Mn 2+ , depending on the presence of MICU1 (Kamer et al., 2018).
Regulation of MCU and of NCLX Affecting Cell Death
Mitochondrial calcium uniport has a documented, crucial role in both proliferation and apoptosis [for reviews see e.g., (De Stefani et al., 2015 Bustos et al., 2017 Cui et al., 2017 Bachmann et al., 2019)]. The expression of the MCU subunit can be post-transcriptionally down-regulated by several small non-coding regulatory RNAs (miR), miR-25, and miR-138 (Marchi et al., 2013 Hong et al., 2017 Jaquenod De Giusti et al., 2018 Figure 1). The miRs drastically decrease MCU protein levels, blocking thus mitochondrial Ca 2+ uptake without affecting [Ca 2+ ]C and [Ca 2+ ]ER, causing reduced apoptosis in cancer cells. These miRs also affect the expression of proapoptotic proteins, like Bim (Zhang et al., 2012), TRAIL (Razumilava et al., 2012), and PTEN (Poliseno et al., 2010).
Similarly to PTP, MCU activity can be regulated by ROS: a highly conserved Cys-97 at the matrix side of MCU was observed to be S-glutathionylated under oxidative stress, leading to enhanced MCU tetramerization and channel activity that, in turn, exacerbates mitochondrial Ca 2+ overload and triggers cell death (Dong et al., 2017).
Other types of PTMs can also regulate MCU. One of the first reported cases envisioned Ca 2+ /calmodulin-dependent protein kinase 2 (CaMK2) as a regulator of MCU, however, this finding has been challenged (Joiner et al., 2012, 2014 Fieni et al., 2014). Moreover, MCU is regulated by the proline-rich tyrosine kinase 2 (Pyk2), accelerating mitochondrial Ca 2+ uptake via Pyk2-dependent MCU phosphorylation and tetrametric MCU channel pore formation under α1-adrenoceptor (α1-AR) signaling.
Furthermore, mitochondrial Ca 2+ uptake is controlled by the modification of MCU regulators. For example, the protein arginine methyltransferase 1 (PRMT1) methylates MICU1 subunit, decreasing its Ca 2+ sensitivity, thus resulting in reduced calcium uptake into the matrix (Madreiter-Sokolowski et al., 2016). Interestingly, it has been observed that the uncoupling proteins 2/3, previously shown to affect mitochondrial calcium handling, were able to ensure the sensitivity of MICU1 to calcium even upon increased methylation activity (Madreiter-Sokolowski et al., 2016). However, this finding does not explain how upregulation of UCP2 expression can protect mitochondria against calcium overload and cells from apoptosis (Pan et al., 2018). Independently of this, a similar interplay between ANT and F-ATP synthase may exist since the mitochondrial lysine (K)-specific methyltransferase (KMT) FAM173B targets the c-subunit of mitochondrial ATP synthase while FAM173A methylates ANT2 and 3 (Maki et al., 2019).
As to NCLX, a recent study illustrates the physiological relevance of its post-translational regulation: adrenergic stimulation of brown adipose tissue was shown to activate mitochondrial Ca 2+ extrusion via the mitochondrial NCLX in a protein kinase A-mediated phosphorylation-dependent manner, in order to prevent cell death despite the sharp increase of [Ca 2+ ]matrix during thermogenesis (Assali et al., 2020). Inhibition of NCLX by the microtubule-associated tau protein implicated in the tauopathies was instead linked to increased death in neurons (Britti et al., 2020). Recent pieces of evidence from NCLX KO mice suggest an anti-apoptotic role exerted by NCLX by preventing mitochondrial Ca 2+ overload (Luongo et al., 2017 Assali et al., 2020).
For Students & Teachers
For Teachers Only
Cells have membranes that allow them to establish and maintain internal environments that are different from their external environments.
Describe the mechanisms that organisms use to maintain solute and water balance.
Describe the mechanisms that organisms use to transport large molecules across the plasma membrane.
Passive transport is the net movement of molecules from high concentration to low concentration with the direct input of metabolic energy.
Passive transport plays a primary role in the import of materials and the export of wastes.
Active transport requires the direct input of energy to move molecules from regions of low concentration to regions of high concentration.
The selective permeability of membranes allows for the formation of concentration gradients of solutes across the membrane.
The process of endocytosis and exocytosis require energy to move large molecules into and out of cells–
- In exocytosis, internal vesicles fuse with the plasma membrane and secrete large macromolecules out of the cell.
- In endocytosis, the cell takes in macromolecules and particulate matter by forming new vesicles derived from the plasma membrane.
Megakaryocyte Development and Platelet Formation
Joseph E. Italiano Jr. , John H. Hartwig , in Platelets (Second Edition) , 2007
1 Demarcation Membrane System
One of the most striking features of a mature megakaryocyte is its elaborate DMS ( Fig. 2-3 ) 33 — an extensive network of membrane channels composed of flattened cisternae and tubules. The suborganization of the megakaryocyte cytoplasm into membrane-delineated “platelet territories” was first reported by Kautz and De Marsh, 34 and a detailed description of these membranes by Yamada 35 soon followed. The DMS is detectable in promegakaryocytes, but becomes most evident in mature megakaryocytes in which it permeates the megakaryocyte cytoplasm, except for a rim of cortical cytoplasm from which it is excluded ( Fig. 2-3 ). It has been proposed that the DMS derives from megakaryocyte plasma membrane in the form of tubular invaginations. 36 The DMS is in contact with the external milieu and can be labeled with extracellular tracers, such as ruthenium red, lanthanum salts, and tannic acid. 37–39 The exact function of this elaborate smooth membrane system has been hotly debated for many years. Initially, it was postulated to play a central role in platelet formation by defining preformed “platelet territories” within the megakaryocyte cytoplasm (discussed later). However, recent studies more strongly suggest that the DMS functions primarily as a membrane reserve for proplatelet formation and extension. The DMS has also been proposed to mature into the OCS of the mature platelet, which functions as a channel for the secretion of granule contents. However, bovine megakaryocytes, which have a well-defined DMS, produce platelets that do not develop an OCS, suggesting that the OCS is not necessarily a remnant of the DMS. 39 , 40
Figure 2-3 . Electron micrograph of a thin section through a mature megakaryocyte having a well-defined demarcation membrane system (DMS). The DMS is a smooth membrane system organized into a network of narrow channels homogeneously distributed throughout the cytoplasm (×5000). The DMS has been proposed to originate from the invagination of plasma membrane and to function as a membrane reservoir for proplatelet formation or as a mechanism to subdivide the megakaryocyte cytoplasm into “platelet fields.”
(From Zucker–Franklin, 33 with permission.)
3.5 Passive Transport
Plasma membranes must allow certain substances to enter and leave a cell, while preventing harmful material from entering and essential material from leaving. In other words, plasma membranes are selectively permeable —they allow some substances through but not others. If they were to lose this selectivity, the cell would no longer be able to sustain itself, and it would be destroyed. Some cells require larger amounts of specific substances than do other cells they must have a way of obtaining these materials from the extracellular fluids. This may happen passively, as certain materials move back and forth, or the cell may have special mechanisms that ensure transport. Most cells expend most of their energy, in the form of adenosine triphosphate (ATP), to create and maintain an uneven distribution of ions on the opposite sides of their membranes. The structure of the plasma membrane contributes to these functions, but it also presents some problems.
The most direct forms of membrane transport are passive. Passive transport is a naturally occurring phenomenon and does not require the cell to expend energy to accomplish the movement. In passive transport, substances move from an area of higher concentration to an area of lower concentration in a process called diffusion. A physical space in which there is a different concentration of a single substance is said to have a concentration gradient .
Plasma membranes are asymmetric, meaning that despite the mirror image formed by the phospholipids, the interior of the membrane is not identical to the exterior of the membrane. Integral proteins that act as channels or pumps work in one direction. Carbohydrates, attached to lipids or proteins, are also found on the exterior surface of the plasma membrane. These carbohydrate complexes help the cell bind substances that the cell needs in the extracellular fluid. This adds considerably to the selective nature of plasma membranes.
Recall that plasma membranes have hydrophilic and hydrophobic regions. This characteristic helps the movement of certain materials through the membrane and hinders the movement of others. Lipid-soluble material can easily slip through the hydrophobic lipid core of the membrane. Substances such as the fat-soluble vitamins A, D, E, and K readily pass through the plasma membranes in the digestive tract and other tissues. Fat-soluble drugs also gain easy entry into cells and are readily transported into the body’s tissues and organs. Molecules of oxygen and carbon dioxide have no charge and pass through by simple diffusion.
Polar substances, with the exception of water, present problems for the membrane. While some polar molecules connect easily with the outside of a cell, they cannot readily pass through the lipid core of the plasma membrane. Additionally, whereas small ions could easily slip through the spaces in the mosaic of the membrane, their charge prevents them from doing so. Ions such as sodium, potassium, calcium, and chloride must have a special means of penetrating plasma membranes. Simple sugars and amino acids also need help with transport across plasma membranes.
Diffusion is a passive process of transport. A single substance tends to move from an area of high concentration to an area of low concentration until the concentration is equal across the space. You are familiar with diffusion of substances through the air. For example, think about someone opening a bottle of perfume in a room filled with people. The perfume is at its highest concentration in the bottle and is at its lowest at the edges of the room. The perfume vapor will diffuse, or spread away, from the bottle, and gradually, more and more people will smell the perfume as it spreads. Materials move within the cell’s cytosol by diffusion, and certain materials move through the plasma membrane by diffusion (Figure 3.20). Diffusion expends no energy. Rather the different concentrations of materials in different areas are a form of potential energy, and diffusion is the dissipation of that potential energy as materials move down their concentration gradients, from high to low.
Each separate substance in a medium, such as the extracellular fluid, has its own concentration gradient, independent of the concentration gradients of other materials. Additionally, each substance will diffuse according to that gradient.
Several factors affect the rate of diffusion.
- Extent of the concentration gradient: The greater the difference in concentration, the more rapid the diffusion. The closer the distribution of the material gets to equilibrium, the slower the rate of diffusion becomes.
- Mass of the molecules diffusing: More massive molecules move more slowly, because it is more difficult for them to move between the molecules of the substance they are moving through therefore, they diffuse more slowly.
- Temperature: Higher temperatures increase the energy and therefore the movement of the molecules, increasing the rate of diffusion.
- Solvent density: As the density of the solvent increases, the rate of diffusion decreases. The molecules slow down because they have a more difficult time getting through the denser medium.
Concepts in Action
For an animation of the diffusion process in action, view this short video on cell membrane transport.
In facilitated transport , also called facilitated diffusion, material moves across the plasma membrane with the assistance of transmembrane proteins down a concentration gradient (from high to low concentration) without the expenditure of cellular energy. However, the substances that undergo facilitated transport would otherwise not diffuse easily or quickly across the plasma membrane. The solution to moving polar substances and other substances across the plasma membrane rests in the proteins that span its surface. The material being transported is first attached to protein or glycoprotein receptors on the exterior surface of the plasma membrane. This allows the material that is needed by the cell to be removed from the extracellular fluid. The substances are then passed to specific integral proteins that facilitate their passage, because they form channels or pores that allow certain substances to pass through the membrane. The integral proteins involved in facilitated transport are collectively referred to as transport proteins, and they function as either channels for the material or carriers.
Osmosis is the movement of free water molecules through a semipermeable membrane according to the water's concentration gradient across the membrane, which is inversely proportional to the solutes' concentration. Whereas diffusion transports material across membranes and within cells, osmosis transports only water across a membrane and the membrane limits the diffusion of solutes in the water. Osmosis is a special case of diffusion. Water, like other substances, moves from an area of high concentration of free water molecules to one of low free water molecule concentration. Imagine a beaker with a semipermeable membrane, separating the two sides or halves (Figure 3.21). On both sides of the membrane, the water level is the same, but there are different concentrations on each side of a dissolved substance, or solute , that cannot cross the membrane. If the volume of the water is the same, but the concentrations of solute are different, then there are also different concentrations of water, the solvent, on either side of the membrane.
A principle of diffusion is that the molecules move around and will spread evenly throughout the medium if they can. However, only the material capable of getting through the membrane will diffuse through it. In this example, the solute cannot diffuse through the membrane, but the water can. Water has a concentration gradient in this system. Therefore, water will diffuse down its concentration gradient, crossing the membrane to the side where it is less concentrated. This diffusion of water through the membrane—osmosis—will continue until the concentration gradient of water goes to zero. Osmosis proceeds constantly in living systems.
Concepts in Action
Watch this video that illustrates diffusion in hot versus cold solutions.
Tonicity describes the amount of solute in a solution. The measure of the tonicity of a solution, or the total amount of solutes dissolved in a specific amount of solution, is called its osmolarity . Three terms—hypotonic, isotonic, and hypertonic—are used to relate the osmolarity of a cell to the osmolarity of the extracellular fluid that contains the cells. In a hypotonic solution, such as tap water, the extracellular fluid has a lower concentration of solutes than the fluid inside the cell, and water enters the cell. (In living systems, the point of reference is always the cytoplasm, so the prefix hypo- means that the extracellular fluid has a lower concentration of solutes, or a lower osmolarity, than the cell cytoplasm.) It also means that the extracellular fluid has a higher concentration of water than does the cell. In this situation, water will follow its concentration gradient and enter the cell. This may cause an animal cell to burst, or lyse.
In a hypertonic solution (the prefix hyper- refers to the extracellular fluid having a higher concentration of solutes than the cell’s cytoplasm), the fluid contains less water than the cell does, such as seawater. Because the cell has a lower concentration of solutes, the water will leave the cell. In effect, the solute is drawing the water out of the cell. This may cause an animal cell to shrivel, or crenate.
In an isotonic solution, the extracellular fluid has the same osmolarity as the cell. If the concentration of solutes of the cell matches that of the extracellular fluid, there will be no net movement of water into or out of the cell. Blood cells in hypertonic, isotonic, and hypotonic solutions take on characteristic appearances (Figure 3.22).
A doctor injects a patient with what the doctor thinks is isotonic saline solution. The patient dies, and autopsy reveals that many red blood cells have been destroyed. Do you think the solution the doctor injected was really isotonic?
Some organisms, such as plants, fungi, bacteria, and some protists, have cell walls that surround the plasma membrane and prevent cell lysis. The plasma membrane can only expand to the limit of the cell wall, so the cell will not lyse. In fact, the cytoplasm in plants is always slightly hypertonic compared to the cellular environment, and water will always enter a cell if water is available. This influx of water produces turgor pressure, which stiffens the cell walls of the plant (Figure 3.23). In nonwoody plants, turgor pressure supports the plant. If the plant cells become hypertonic, as occurs in drought or if a plant is not watered adequately, water will leave the cell. Plants lose turgor pressure in this condition and wilt.
Thomas Dean Pollard is a prominent educator, cell biologist and biophysicist whose research focuses on understanding cell motility through the study of actin filaments and myosin motors. He is Sterling Professor of Molecular, Cellular & Developmental Biology and a Professor of Cell Biology and Molecular Biophysics & Biochemistry at Yale University. He was Dean of Yale's Graduate School of Arts and Sciences from 2010 to 2014, and President of the Salk Institute for Biological Studies from 1996 to 2001. Pollard is very active in promoting scientific education and research primarily through two major societies, both of which he is a past President: the American Society for Cell Biology and the Biophysical Society
Affiliations and Expertise
Sterling Professor, Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT
William Charles Earnshaw is Professor of Chromosome Dynamics at the University of Edinburgh where he has been a Wellcome Trust Principal Research Fellow since 1996. Earnshaw is an elected Fellow of the Royal Society since 2013 for his studies of mitotic chromosome structure and segregation. Before Edinburgh, he was Professor of Cell Biology and Anatomy at Johns Hopkins School of Medicine.
Affiliations and Expertise
Professor and Wellcome Trust Principal Research Fellow, Wellcome Trust Centre for Cell Biology, ICB, University of Edinburgh, Scotland, United Kingdom
Jennifer Lippincott-Swartz is Group Leader at the Howard Hughes Medical Institute Janelia Research Campus. Her lab uses live cell imaging approaches to analyze the spatio-temporal behaviour and dynamic interactions of molecules in cells with a special focus on neurobiology. Before Janelia, Lippincott-Swartz was a primary investigator and chief of the Section on Organelle Biology in the Cell Biology and Metabolism Branch. Her work there included a collaboration with physicists Eric Betzig and Harald Hess (now group leaders at Janelia), who proposed a new function for the photoactivatable protein. The scientists used the protein to generate photoactivatable fluorophores, or dyes, which enabled them to illuminate different sets of molecules sequentially, creating a microscope image far more detailed than previously possible. The method, called super-resolution microscopy, garnered Betzig the 2014 Nobel Prize in Chemistry.
Affiliations and Expertise
Group Leader, Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, Virginia, United States
Graham Johnson is a computational biologist and Certified Medical Illustrator (CMI) with approx. 20 years of professional experience. He is Director of the Animated Cell at the Allen Institute. Before the Allen Institute, Johnson’s lab in the California Institute for Quantitative Biosciences at the University of California, San Francisco worked to generate, simulate and visualize molecular models of cells. His lab’s Mesoscope project and his team at Allen Institute continue this mission by uniting biologists, programmers and artists to interoperate the computational tools of science and art.
Affiliations and Expertise
Director, Animated Cell, Allen Institute for Cell Biology, Seattle, Washington, QB3 Faculty Fellow, University of California, San Francisco, San Francisco, California