Melvin Bae2nd Faculty of medicine

2014

Basic principles Ion flux; driven by force of diffusion

and/ or electrostatic forces

Ions diffuse through channels ( „Leak channels“ ) =constantly open

-> no further impuls needed

Gated channels

-> signal needed

Ion channels in each of living cell

Ions flow „downhill“ towards the concentration gradient

=CHANNEL

Ions flow „uphill“ against the concentrationgradient (energy needed)

= PUMP/TRANSPORTER

Membrane potential via Goldman-Hodgkin-Katz equation (GHK equation) (expansion of Nernst equation = only single Ion type)

Over 300 diferent ion channel types

Aprox. 107 ions / per second / per channel

Basic principles

Basic mechanisms

Silbernagl; Taschenatlas Physiologie

Main functions 1.) Ion concentraion sets up resting potential :

- Na+ open Depolarization

- K+ open Re- and Hyperpolarization

Main functions 2.) Volume Regulation and Salt balance:

- Ion flux controles electrolyte distribution

- Across epithel (basal labyrinth - typical)

- Examples : gut, kidney, sweat glands or the choroid plexus.

Main functions 3.)

hormone secretion,

neurotransmitter release,

muscle contraction

Morphology of ion channels

Sodium channels 9 known in human being

(E.g. Neurons, myocites, glia cells )

big integral protein structure, ca 300kD, aprox 0,3-0,5 nm diameter

Pore just big enough for 1 Na+ with one associated H2O molecule

Compartements of a channel

- Ion conductiong pore

- Gate

- Sensor

Potassium Channels

Potassium Channels1. (Ion) Ligand gated (e.g. Ca++)

2. Mechanical (e.g. tip links; stereocilia; inner hair cell -> ear )

3. G Protein –(e.g. in cardiac muscle)

4. (Metabolite) Ligand (e.g ATP reactive Beta cells)

- Voltage gated K+ channels , only have open – closed state

- ( Na+ =O/C/I)

Blockers

-> Tetraethylamoniom closes K+ Channels ;

-> further more over 40 peptides from scorpion toxins;

-> Apamin (Toxin of bees)

Potassium Channels Example of Potassium-channel regulated hormone

secretion in the Beta Cells in the Langerhans islands (pancreas)

Resting potential

Necessary to maintain the electrochemical gradient : pumps and transporters

Patch clamp method

Refinement of voltage clamp method by Hodgkin and Huxley – nobel price (1952)

Possible to measure selectively the Ion current through channels

Hollow end pipette 0,3-3 micrometer -> small membrane area selcected/torn out and isolated

Similar to the programm which we had in class !!

Experiments with channel blocking drugs:

-> Tetradotoxin = blocks Na channels

-> Tetrathylammonium = blocks K Channels

Patch clamp method

Calcium channelse.g. In Cardiac and smooth muscle cells, Presynpatic terminals etc.

Flux inside the cell/ to ER

Ca2+ (free)

EC= 2.5 mmol/L

IC = 0.1 micromol/L

5 types of Voltage gated Ca2+ channels

Type

L – Type(Long-lasting)

High Voltage

Skelettal muscle, smooth muscle, osteoblasts

P(Purkinje)

HV Purkinje cells

N(Neural)

HV Brain and PNS,(presynaptic terminal )

R(Residual)

IntermediateVoltage

Cerebellar granule cells

T(Transient)

Low Voltage

Pacemaker activity,osteocytes

Presynaptic terminal

Ligand gated Ion channel in Postsynaptic terminal

Cation channel ( Na+ or K+)

- Lined with neg. charge, entrance becomes a bit larger

- lets e.g. hydrated Na+ ions inside

- -> excitatory

Anion channel (Cl-)

- Pos charged, opens , influx of Cl-

- ->Inhibitory

Ligand gated Ca2+ Channels

Examples:

cAMP ( of myocard cells)

IP3 (Inositol Triphosphat) for IC Ca2+ depots

Ion channels in Sperms ( Cation)

-> functionally necessary for fertility and also fertilization

Ca2+ can function itself as an intracellulary transmitter which opens K+ channels or „fast“ Na+ channels (Silbernagl)

Division of Endocrinology, Central Drug Research Institute, Lucknow, UP, India.

Cardiac muscle

Already if Ca2+ drops 50% -> muscle tetany (lethal if respiratory)

Skeletal muscle

Chloride channels

Approximately 13 types

Neurones e.g. GABA ligand gated

Skeletal, cardiac and smooth muscle,

Cell volume regulation

E.g. CLC type (10-12 transmembrane helices)

-> CLC1 involved in reestablising resting membrane potential in skeletal muscle cells

Also -> solute concentration mechanism in the kidneys

(abnormal function in thick ascending loop of Henle, associated with Bartter´s syndrom renal salt wasting )

Cl- channels

- transepithelial salt transport,

Or cystic fibrosis transmembrane conductance regulator (CFTR) gene

cystic fibrosis

Genetic disorder

Gland secretions are abnormally thick

Chloride Ion Channels may be targeted as a treatment for some Respiratory Diseases by regulating abnormal mucus production.

Cl- channels

Thank you for your attention !

Ion channel openers / closers

OPENERS

Diazoxide

-vasodilator used for hypertension, smooth muscle relaxing activity

CLOSERS

Amiodarone

- Used to treat cardiac arrhythmias , prolonging the repolarization

Yellow – inGrey - out

Sourceshttp://www.creative-biogene.com/images/Ion-Channel.jpghttp://en.wikipedia.org/wiki/Membrane_potential#mediaviewer/File:Basis_of_Membrane_Potential2.pnghttp://www.nature.com/scitable/content/ne0000/ne0000/ne0000/ne0000/14615258/f1_marban_415213a-f1.2.jpghttp://www1.appstate.edu/~kms/classes/psy3203/Ear/hair_cell_tip.jpghttp://www.medbio.info/images/Time%203-4/wpeozyop.gifhttp://upload.wikimedia.org/wikipedia/commons/thumb/e/e0/Synapse_Illustration2_tweaked.svg/2000px-Synapse_Illustration2_tweaked.svg.pnghttps://www3.nd.edu/~aseriann/nak.gifhttp://www.uibk.ac.at/pharmazie/pharmakologie/images/cachannel.gif?m=ehttp://www.neurology.org/content/68/3/233/F1.large.jpghttp://en.wikipedia.org/wiki/Sodium_channel#mediaviewer/File:Sodium_channel_phylogram.png = evolution of those channelshomepage: Alexander Chew:Florida State University;BSC5936;February 2005http://upload.wikimedia.org/wikipedia/commons/4/45/GABAA-receptor-protein-example.pnghttp://cbsnews1.cbsistatic.com/hub/i/r/2010/09/22/86b3c5fb-a643-11e2-a3f0-029118418759/resize/620x465/9f5987c0e770cce5ce393581bd1aac6e/sperm_1.jpghttp://upload.wikimedia.org/wikipedia/commons/8/81/1ots_opm.pngSource: Mizutani S , "Milestones in the Evolution of the Study of Arrhythmias"http://circep.ahajournals.org/content/2/2/185/F1.large.jpg Literature: (german book edition) Silbernagl; Taschenatlas Physiologieguyton & Hall : textbook medical physiology(german book edition) Golenhofen; Basislehrbuch physiologie (4th edition)