DOCSLIB.ORG

Correlations in Ion Channel Expression Emerge from PNAS PLUS Homeostatic Tuning Rules

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Correlations in Ion Channel Expression Emerge from PNAS PLUS Homeostatic Tuning Rules Correlations in ion channel expression emerge from PNAS PLUS homeostatic tuning rules Timothy O’Leary1, Alex H. Williams, Jonathan S. Caplan, and Eve Marder1 Volen Center for Complex Systems, Department of Biology, Brandeis University, Waltham, MA 02454 Contributed by Eve Marder, May 29, 2013 (sent for review April 24, 2013) Experimental observations reveal that the expression levels of dif- a homeostatic tuning rule) were made from random sets of con- ferent ion channels vary across neurons of a defined type, even ductance parameters and then searched for those that produce a when these neurons exhibit stereotyped electrical properties. How- specific behavior, they did not show correlations in conductance ever, there are robust correlations between different ion channel expression that resemble the experimental findings (37). This find- expression levels, although the mechanisms that determine these ing raised the question of how the correlations seen in the experi- correlations are unknown. Using generic model neurons, we show mental data are established and whether they are somehow that correlated conductance expression can emerge from simple homeostatic control mechanisms that couple expression rates of genetically hardwired. For example, correlations in ion channel individual conductances to cellular readouts of activity. The correla- expression may simply result from explicit coregulation, such as tions depend on the relative rates of expression of different con- control of gene expression by a common transcription factor or ductances. Thus, variability is consistent with homeostatic regulation silencing of a subset of genes in a certain population of cells. and the structure of this variability reveals quantitative relations be- Another possibility is that correlations emerge from some in- tween regulation dynamics of different conductances. Furthermore, teraction between activity-dependent regulatory processes that we show that homeostatic regulation is remarkably insensitive to the control the expression of different ion channel types. details that couple the regulation of a given conductance to overall We address this question in this paper using theory and compu- neuronal activity because of degeneracy in the function of multiple tational models. We show that correlations in ion channel expres- conductances and can be robust to “antihomeostatic” regulation of sion emerge as a consequence of homeostatic control mechanisms NEUROSCIENCE a subset of conductances expressed in a cell. that couple the expression rates of individual conductances to a cell- intrinsic readout of activity. Importantly, the shape of the correla- neuronal excitability | robustness | computational models | control theory tion pattern is determined by the relative rates of expression of different conductances. Furthermore, we show how degeneracy he electrophysiological signature of every neuron is determined Tby the number and kind of voltage-dependent conductances implies that regulatory control mechanisms do not need to be as in its membrane. Most neurons express many voltage-dependent precisely tuned as previously anticipated. For example, subsets of conductances, some of which may have overlapping or degenerate conductances can be regulated antihomeostatically without in- physiological functions (1–6). Furthermore, neurons in the brains terfering with convergence to a target activity level, meaning that of long-lived animals must maintain reliable function over the inward conductances can up-regulate in response to elevated animal’s lifetime while all of their ion channels and receptors are activity and vice versa for outward conductances. Thus, there is replaced in the membrane over hours, days, or weeks. Conse- considerable flexibility in how different conductances can be quently, ongoing turnover of ion channels of various types must regulated while maintaining a “set point” in activity. This flexi- occur without compromising the essential excitability properties bility is compatible with distinct correlation patterns seen in the – of the neuron (5, 7 10). conductance expression of different neuron types. Both theoretical and experimental studies suggest that main- taining stable intrinsic excitability is accomplished via homeostatic, 2+ negative feedback processes that use intracellular Ca concen- Significance trations as a sensor of activity and then alter the synthesis, in- sertion, and degradation of membrane conductances to achieve a target activity level (11–27). Among the modeling studies are A deep puzzle in neuroscience is how neurons maintain their electrical properties despite continuous ion channel turnover several different homeostatic tuning rules that differ in how sensor and activity perturbations. Previous work proposed that ac- readout is coupled to the changes in conductance necessary to tivity-dependent homeostatic rules ensure robust development achieve a target activity (11, 13, 14, 28). Regardless, these models of excitability by regulating channel density, although it is not can self-assemble from randomized initial conditions, and they will understood how these rules shape the distribution of ion change their conductance densities in response to perturbation or channel types nor how finely tuned these rules must be. We synaptic drive. In one of these homeostatic self-tuning models (14), show that generic homeostatic regulation rules impose corre- similar activity patterns can be associated with different sets of lations in the steady-state distribution of ion channels, as has conductance densities. been recently observed experimentally. Specific correlations Thus, it is perhaps not surprising that experimental studies also fi depend on relative expression rates, and the regulation rules nd a considerable range in the conductance densities of voltage- themselves are far more robust than previously thought. dependent channels and in the mRNA expression of their ion – channel genes (29 36). The experimental studies also showed clear Author contributions: T.O. and E.M. designed research; T.O., A.H.W., and J.S.C. performed correlations in these expression patterns (30, 32–35); for example, research; T.O., A.H.W., and J.S.C. analyzed data; and T.O. and E.M. wrote the paper. strong linear correlations are found between mRNA copy number The authors declare no conflict of interest. for shal/A-type potassium channels and IH/hyperpolarization/ Freely available online through the PNAS open access option. fi cyclic nucleotide activated channels in identi ed crustacean 1To whom correspondence may be addressed. E-mail: [email protected] or marder@ motor neurons. It is therefore possible that these correlations are brandeis.edu. crucial for the electrophysiological behavior of the neuron in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. question. However, when large numbers of model neurons (without 1073/pnas.1309966110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1309966110 PNAS Early Edition | 1of10 Downloaded by guest on September 26, 2021 Results steeper rates of change in this case. In both of these versions of the 2+ There are several existing homeostatic neuron models that use model, [Ca ] equilibrates at its target value. Interestingly, 2+ intracellular Ca concentrations to regulate their conductances when we changed the sign of g2 (thus making its direction of (11, 13, 14, 18, 28, 38). These models are capable of producing and regulation antihomeostatic), the model also converges to target 2+ maintaining complex activity patterns such as rhythmic bursting [Ca ] value. In fact, homeostatic models with multiple con- that rely on the interactions between many voltage-dependent ductances can tolerate such antihomeostatic regulation in conductances and Ca2+ dynamics. Analysis of these models is of- a subset of conductances provided broad constraints on the τ ten mathematically intractable, and it is also difficult to develop an regulation rates ( i) are respected. fl intuitive understanding of how the distribution of conductances How do the regulation rates in uence the resulting steady-state is shaped over time. Therefore, in this study we start with a toy distribution of conductances? Fig. 1D shows three views of a 3D model with three non–voltage-dependent conductances and simple plot showing the conductances as they are distributed initially (or- Ca2+ dynamics. We then progress to a more complicated spiking ange points) and at steady state. Each version of the model (with model with three regulated voltage-dependent conductances and different sets of regulation rates) converges to a distinct region of finish with an analysis of an existing model that has seven voltage- conductance space, but these regions sit on a common plane (pink dependent conductances and three distinct [Ca2+] sensors. In all rectangle). This plane is simply the solution set of all conductances three cases, we examine how the correlations in the steady-state that produce target activity in the model. Thus, the regulation rates conductance distributions are shaped by the parameters that (as well as the initial values of the conductances) determine the govern regulation. We find that the intuition developed in the direction in which the model evolves in conductance space, whereas simplest model carries over to more complex cases. the point of intersection of each trajectory with the solution plane dictates the steady-state conductance values. Correlations Arise in Simple Model of Homeostatic The correlation between
Load more

Recommended publications
  • Glossary - Cellbiology
    1 Glossary - Cellbiology Blotting: (Blot Analysis) Widely used biochemical technique for detecting the presence of specific macromolecules (proteins, mRNAs, or DNA sequences) in a mixture. A sample first is separated on an agarose or polyacrylamide gel usually under denaturing conditions; the separated components are transferred (blotting) to a nitrocellulose sheet, which is exposed to a radiolabeled molecule that specifically binds to the macromolecule of interest, and then subjected to autoradiography. Northern B.: mRNAs are detected with a complementary DNA; Southern B.: DNA restriction fragments are detected with complementary nucleotide sequences; Western B.: Proteins are detected by specific antibodies. Cell: The fundamental unit of living organisms. Cells are bounded by a lipid-containing plasma membrane, containing the central nucleus, and the cytoplasm. Cells are generally capable of independent reproduction. More complex cells like Eukaryotes have various compartments (organelles) where special tasks essential for the survival of the cell take place. Cytoplasm: Viscous contents of a cell that are contained within the plasma membrane but, in eukaryotic cells, outside the nucleus. The part of the cytoplasm not contained in any organelle is called the Cytosol. Cytoskeleton: (Gk. ) Three dimensional network of fibrous elements, allowing precisely regulated movements of cell parts, transport organelles, and help to maintain a cell’s shape. • Actin filament: (Microfilaments) Ubiquitous eukaryotic cytoskeletal proteins (one end is attached to the cell-cortex) of two “twisted“ actin monomers; are important in the structural support and movement of cells. Each actin filament (F-actin) consists of two strands of globular subunits (G-Actin) wrapped around each other to form a polarized unit (high ionic cytoplasm lead to the formation of AF, whereas low ion-concentration disassembles AF).
    [Show full text]
  • Biopsychology 2012 – Sec 003 (Dr
    Biopsychology 2012 – sec 003 (Dr. Campeau) Study Guide for First Midterm What are some fun facts about the human brain? - there are approximately 100 billion neurons in the brain; - each neuron makes between 1000 to 10000 connections with other neurons; - speed of action potentials varies from less than 1 mph and up to 100 mph. What is a neuron? A very specialized cell type whose function is to receive, process, and send information; these cells are found in the central nervous system (CNS – brain, spinal cord, retina) and the peripheral nervous system (PNS – the rest of the body). What is a nerve? They are axons of individual neurons in bundles or strands of many axons. What are the major parts of a neuron? - cell membrane: “skin” of the neuron; - cytoplasm: everything inside the skin; - nucleus: contains chromosomes (DNA); - ribosomes: generate proteins from mRNA; - mitochondria: energy “generator” of cells (produce ATP); - mitochondria: moves “stuff” inside the neuron (like a tow rope); - soma: cell body, excluding dendrites and axons; - dendrites and spines: part of the neuron usually receiving information from other neurons; - axons: part of the neuron that transmits information to other neurons; - myelin sheath: surrounds axons and provides electrical “insulation”; - nodes of Ranvier: small area on axons devoid of myelin sheath; - presynaptic terminal: area of neuron where neurotransmitter is stored and released by action potentials. What are the different neuron types according to function? 1. Sensory neurons: neurons specialized to “receive” information about the environment. 2. Motor neurons: neurons specialized to produce movement (contraction of muscles). 3. Interneurons or Intrinsic neurons: neurons, usually with short axons, that handle local information.
    [Show full text]
  • Nernst Potentials and Membrane Potential Changes
    UNDERSTANDING MEMBRANE POTENTIAL CHANGES IN TERMS OF NERNST POTENTIALS: For seeing how a change in conductance to ions affects the membrane potential, follow these steps: 1. Make a graph with membrane potential on the vertical axis (-100 to +55) and time on the horizontal axis. 2. Draw dashed lines indicating the standard Nernst potential (equilibrium potential) for each ion: Na+ = +55 mV, K+ = -90mV, Cl- = -65 mV. 3. Draw lines below the horizontal axis showing the increased conductance to individual ions. 4. Start plotting the membrane potential on the left. Most graphs will start at resting potential (-70 mV) 5. When current injection (Stim) is present, move the membrane potential upward to Firing threshold. 6. For the time during which membrane conductance to a particular ion increases, move the membrane potential toward the Nernst potential for that ion. 7. During the time when conductance to a particular ion decreases, move the membrane potential away from the Nernst potential of that ion, toward a position which averages the conductances of the other ions. 8. When conductances return to their original value, membrane potential will go to its starting value. +55mV ACTION POTENTIAL SYNAPTIC POTENTIALS 0mV Membrane potential Firing threshold Firing threshold -65mV -90mV Time Time Na+ K+ Conductances Stim CHANGES IN MEMBRANE POTENTIAL ALLOW NEURONS TO COMMUNICATE The membrane potential of a neuron can be measured with an intracellular electrode. This 1 provides a measurement of the voltage difference between the inside of the cell and the outside. When there is no external input, the membrane potential will usually remain at a value called the resting potential.
    [Show full text]
  • Neurotransmitter Actions
    Central University of South Bihar Panchanpur, Gaya, India E-Learning Resources Department of Biotechnology NB: These materials are taken/borrowed/modified/compiled from various resources like research articles and freely available internet websites, and are meant to be used solely for the teaching purpose in a public university, and for serving the needs of specified educational programmes. Dr. Jawaid Ahsan Assistant Professor Department of Biotechnology Central University of South Bihar (CUSB) Course Code: MSBTN2003E04 Course Name: Neuroscience Neurotransmitter Actions • Excitatory Action: – A neurotransmitter that puts a neuron closer to an action potential (facilitation) or causes an action potential • Inhibitory Action: – A neurotransmitter that moves a neuron further away from an action potential • Response of neuron: – Responds according to the sum of all the neurotransmitters received at one time Neurotransmitters • Acetylcholine • Monoamines – modified amino acids • Amino acids • Neuropeptides- short chains of amino acids • Depression: – Caused by the imbalances of neurotransmitters • Many drugs imitate neurotransmitters – Ex: Prozac, zoloft, alcohol, drugs, tobacco Release of Neurotransmitters • When an action potential reaches the end of an axon, Ca+ channels in the neuron open • Causes Ca+ to rush in – Cause the synaptic vesicles to fuse with the cell membrane – Release the neurotransmitters into the synaptic cleft • After binding, neurotransmitters will either: – Be destroyed in the synaptic cleft OR – Taken back in to surrounding neurons (reuptake) Excitable cells: Definition: Refers to the ability of some cells to be electrically excited resulting in the generation of action potentials. Neurons, muscle cells (skeletal, cardiac, and smooth), and some endocrine cells (e.g., insulin- releasing pancreatic β cells) are excitable cells.
    [Show full text]
  • Electrical Activity of the Heart: Action Potential, Automaticity, and Conduction 1 & 2 Clive M
    Electrical Activity of the Heart: Action Potential, Automaticity, and Conduction 1 & 2 Clive M. Baumgarten, Ph.D. OBJECTIVES: 1. Describe the basic characteristics of cardiac electrical activity and the spread of the action potential through the heart 2. Compare the characteristics of action potentials in different parts of the heart 3. Describe how serum K modulates resting potential 4. Describe the ionic basis for the cardiac action potential and changes in ion currents during each phase of the action potential 5. Identify differences in electrical activity across the tissues of the heart 6. Describe the basis for normal automaticity 7. Describe the basis for excitability 8. Describe the basis for conduction of the cardiac action potential 9. Describe how the responsiveness relationship and the Na+ channel cycle modulate cardiac electrical activity I. BASIC ELECTROPHYSIOLOGIC CHARACTERISTICS OF CARDIAC MUSCLE A. Electrical activity is myogenic, i.e., it originates in the heart. The heart is an electrical syncitium (i.e., behaves as if one cell). The action potential spreads from cell-to-cell initiating contraction. Cardiac electrical activity is modulated by the autonomic nervous system. B. Cardiac cells are electrically coupled by low resistance conducting pathways gap junctions located at the intercalated disc, at the ends of cells, and at nexus, points of side-to-side contact. The low resistance pathways (wide channels) are formed by connexins. Connexins permit the flow of current and the spread of the action potential from cell-to-cell. C. Action potentials are much longer in duration in cardiac muscle (up to 400 msec) than in nerve or skeletal muscle (~5 msec).
    [Show full text]
  • The Excitable Cell. Resting Membrane Potential and Action Potential (1&2)
    The excitable cell. Resting Membrane Potential and Action Potential (1&2) Dr Sergey Kasparov School of Medical Sciences, Room E9 THIS TOPIC IS ALSO COVERED IN TUTORIALS! Teaching home page: http://www.bristol.ac.uk/phys-pharm/media/teaching/ Why do we call these cells “excitable”? Real action potentials.avi The key point: Bioelectricity is generated by the ions moving across cellular membranes Concentration of selected solutes in intracellular fluid and extracellular fluid in millimols mM 160 140 120 100 Insi de the cell 80 60 In extracellular fluid 40 20 0 1 The Na+/K+ pump outside inside [[mMmM]] + + [[mMmM]] + + + + + + + Na 145 + + 15 + K 4 + + 140 ATPATP ••isis an active ion transporter (ATP‐dependent) ••isis responsible for creating and upholding Na+ and K+ concentration gradients ••isis electrogenic – pumps 3 Na+ versus 2 K+ ions Reminder: Movement of ions is affected by concentration gradient and the electrical field Chemical driving force _ _ + + _ + + Electrical driving force _ + + _ + + + _+ _ + _ + + + + _ + _ + _ + + _ Net flux + + + + _ + _ + + V REMINDER: Diffusion through Ion Channels A leak channel A gated channel Both leak and gated channels allow movement of molecules (mainly inorganic ions) down the electrochemical gradient. So, if the gradient reverses, the ions will flow in the opposite direction. 1. The channels are aqueous pores through the membrane. 2. The channels are usually quite selective, for example some only pass Na+, others K+, still others – Cl- 3. Gated channels may be opened or closed by various factors
    [Show full text]
  • The Action Potential
    See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/6316219 The action potential ARTICLE in PRACTICAL NEUROLOGY · JULY 2007 Source: PubMed CITATIONS READS 16 64 2 AUTHORS, INCLUDING: Mark W Barnett The University of Edinburgh 21 PUBLICATIONS 661 CITATIONS SEE PROFILE Available from: Mark W Barnett Retrieved on: 24 October 2015 192 Practical Neurology HOW TO UNDERSTAND IT Pract Neurol 2007; 7: 192–197 The action potential Mark W Barnett, Philip M Larkman t is over 60 years since Hodgkin and called ion channels that form the permeation Huxley1 made the first direct recording of pathways across the neuronal membrane. the electrical changes across the neuro- Although the first electrophysiological nal membrane that mediate the action recordings from individual ion channels were I 2 potential. Using an electrode placed inside a not made until the mid 1970s, Hodgkin and squid giant axon they were able to measure a Huxley predicted many of the properties now transmembrane potential of around 260 mV known to be key components of their inside relative to outside, under resting function: ion selectivity, the electrical basis conditions (this is called the resting mem- of voltage-sensitivity and, importantly, a brane potential). The action potential is a mechanism for quickly closing down the transient (,1 millisecond) reversal in the permeability pathways to ensure that the polarity of this transmembrane potential action potential only moves along the axon in which then moves from its point
    [Show full text]
  • Neuronal Signaling Neuroscience Fundamentals > the Nerve Cell > the Nerve Cell
    Neuronal Signaling Neuroscience Fundamentals > The Nerve Cell > The Nerve Cell NEURONAL SIGNALING SUMMARY ACTION POTENTIALS See: Action Potentials Key Features • All-or-nothing events • Self-propagating • Conduction speed determined by axon diameter (thicker means faster) and amount of myelination (more myelin means faster transmission). CHEMICAL SYNAPSE Steps of Chemical Synapsis 1) The action potential travels down axon of presynaptic neuron. 2) Vesicle fuses with plasma membrane and releases neurotransmitter into the synaptic cleft. 3) Neurotransmitters bind to ligand-gated ion channels, opening them. 4) Ions entering through the open channels cause a depolarization of the membrane, opening voltage-gated ion channels. 5) Ions pass through these voltage-gated ion channels, causing further depolarization of the membrane. 6) This depolarization (action potential) travels along the membrane as more voltage-gated ion channels are opened. ELECTRICAL SYNAPSE • Cytoplasms of adjacent neurons are connected, allowing ions (and action potentials) to travel directly to the next cell. NEURONAL CODING OF STIMULUS STRENGTH Action Potential Frequency • Stimulus strength is based on frequency of action potentials. Action Potential Strength • Strong stimuli can produce another action potential during the relative refractory period. 1 / 7 ABSOLUTE REFRACTORY PERIOD No further action potentials • Voltage-gated sodium channels are open or inactivated so another stimulus, no matter its strength, CANNOT elicit another action potential. RELATIVE REFRACTORY
    [Show full text]
  • A Simple Description of Biological Transmembrane Potential from Simple Biophysical Considerations and Without Equivalent Circuits
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.02.073635; this version posted May 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A simple description of biological transmembrane potential from simple biophysical considerations and without equivalent circuits Marco Arieli Herrera-Valdez1; 1 Systems Physiology Laboratory, Department of Mathematics, Facultad de Ciencias, Universidad Nacional Autónoma de México, CDMX, México. [email protected] Abstract Biological membranes mediate different physiological processes necessary for life, including but not limited to electrical signalling, volume regulation, and other different forms of communica- tion within and between cells. Ion movement is one of the physical processes underlying many of such processes. In turn, the difference between the electrical potentials around a biological membrane, called transmembrane potential, or membrane potential for short, is one of the key biophysical variables affecting ion movement. Most of the equations available to describe the change in membrane potential are based on analogies with resistive-capacitative electrical circuits. These equivalent circuit models were originally proposed in seminal studies dating back to 1872, and possibly earlier, and assume resistance and capacitance as measures of the permeable and the impermeable properties of the membrane, respectively. These models have been successful in shedding light on our understanding of electrical activity in cells, especially at times when the basic structure, biochemistry and biophysics of biological membrane systems were not well known.
    [Show full text]
  • Membrane Potentials As Signals
    Membrane Potentials as Signals The membrane potential allows a cell to function as a battery, providing electrical power to activities within the cell and between cells. KEY POINTS A membrane potential is the difference in electrical potential between the interior and the exterior of a biological cell. In electrically excitable cells, changes in membrane potential are used for transmitting signals within the cell. The opening and closing of ion channels can induce changes from the resting potential. Depolarization is when the interior voltage becomes more positive and hyperpolarization when it becomes more negative. TERMS Graded potentials Graded potentials vary in size and arise from the summation of the individual actions of ligand- gated ion channel proteins, and decrease over time and space. Depolarization Depolarization is a change in a cell's membrane potential, making it more positive, or less negative, and may result in generation of an action potential. Action potential A short term change in the electrical potential that travels along a cell such as a nerve or muscle fiber. EXAMPLE In neurons, a sufficiently large depolarization can evoke an action potential in which the membrane potential changes rapidly. Give us feedback on this content: Membrane potential (also transmembrane potential or membrane voltage) is the difference in electrical potential between the interior and the exterior of a biological cell. All animal cells are surrounded by a plasma membrane composed of a lipid bilayer with a variety of types of proteins embedded in it. The membrane serves as both an insulator and a diffusion barrier to the movement of ions.
    [Show full text]
  • NOCICEPTORS and the PERCEPTION of PAIN Alan Fein
    NOCICEPTORS AND THE PERCEPTION OF PAIN Alan Fein, Ph.D. Revised May 2014 NOCICEPTORS AND THE PERCEPTION OF PAIN Alan Fein, Ph.D. Professor of Cell Biology University of Connecticut Health Center 263 Farmington Ave. Farmington, CT 06030-3505 Email: [email protected] Telephone: 860-679-2263 Fax: 860-679-1269 Revised May 2014 i NOCICEPTORS AND THE PERCEPTION OF PAIN CONTENTS Chapter 1: INTRODUCTION CLASSIFICATION OF NOCICEPTORS BY THE CONDUCTION VELOCITY OF THEIR AXONS CLASSIFICATION OF NOCICEPTORS BY THE NOXIOUS STIMULUS HYPERSENSITIVITY: HYPERALGESIA AND ALLODYNIA Chapter 2: IONIC PERMEABILITY AND SENSORY TRANSDUCTION ION CHANNELS SENSORY STIMULI Chapter 3: THERMAL RECEPTORS AND MECHANICAL RECEPTORS MAMMALIAN TRP CHANNELS CHEMESTHESIS MEDIATORS OF NOXIOUS HEAT TRPV1 TRPV1 AS A THERAPEUTIC TARGET TRPV2 TRPV3 TRPV4 TRPM3 ANO1 ii TRPA1 TRPM8 MECHANICAL NOCICEPTORS Chapter 4: CHEMICAL MEDIATORS OF PAIN AND THEIR RECEPTORS 34 SEROTONIN BRADYKININ PHOSPHOLIPASE-C AND PHOSPHOLIPASE-A2 PHOSPHOLIPASE-C PHOSPHOLIPASE-A2 12-LIPOXYGENASE (LOX) PATHWAY CYCLOOXYGENASE (COX) PATHWAY ATP P2X RECEPTORS VISCERAL PAIN P2Y RECEPTORS PROTEINASE-ACTIVATED RECEPTORS NEUROGENIC INFLAMMATION LOW pH LYSOPHOSPHATIDIC ACID Epac (EXCHANGE PROTEIN DIRECTLY ACTIVATED BY cAMP) NERVE GROWTH FACTOR Chapter 5: Na+, K+, Ca++ and HCN CHANNELS iii + Na CHANNELS Nav1.7 Nav1.8 Nav 1.9 Nav 1.3 Nav 1.1 and Nav 1.6 + K CHANNELS + ATP-SENSITIVE K CHANNELS GIRK CHANNELS K2P CHANNELS KNa CHANNELS + OUTWARD K CHANNELS ++ Ca CHANNELS HCN CHANNELS Chapter 6: NEUROPATHIC PAIN ANIMAL
    [Show full text]
  • Ion Transport, Resting Potential, and Cellular Homeostasis Introduction
    BIOEN 6003 Lecture Notes 1 Ion Transport, Resting Potential, and Cellular Homeostasis Introduction These notes cover the basics of membrane composition, transport, resting potential, and cellular homeostasis. After a brief introduction to the first two topics, we will spend most of our time on the 3rd and 4th. We will discuss ions that are subject both to diffusion and to an electric field. Current flux in this case is described by a nonlinear partial differential equation (PDE), the Nernst-Planck equation. Under equilibrium conditions (i.e., with no flux) the Nernst-Planck equation can be simplified to give the Nernst equation, a simple algebraic formula that we can use to calculate the value of membrane potential at which a given ion undergoes no net flux. We will derive a circuit-theory-based model of steady-state, non-equilibrium conditions in multi-ion systems. We will also discuss how ionic pumps can be accounted for mathematically. Because of limitations in time, we will not examine several important and interesting questions related to this material. We will skip several classic and important derivations (e.g., derivations of conductance in semi-permeable membranes, and the time- and length-scales over which the condition of electroneutrality applies). Hille is a terrific book, but it does not cover this material that well. The best detailed derivation of these results I have seen is in Weiss, Cellular Biophysics, Vol. 1, MIT Press. Composition of cell membranes 1. The lipid bilayer, composed of phospholipids (polar heads, hydrophobic tails). Bilayer is the most stable structure in a charged aqueous environment.
    [Show full text]