The Sodium-Potassium Pump

• Consists of molecules in the neuronal membrane

• Exchanges NA+ ions for K+ ions across the membrane

• Requires energy for active transport of ions across the membrane

Membrane Permeability Determines Membrane Voltage

Membrane Voltage Determines Membrane Permeability

Stimulator

++ + + +

+++

Depolarize the Neuron

Question: Why does a voltage change across the membrane change membrane permeability?

Answer: There are voltage-gated ion channelsembedded in the membrane. a. Proteins in the membrane b. 100,000 ions/sec can pass through c. Squid axon: 100-600 NA+ channels in 1.0 square micron of membrane d. Selectivity filter and gate

Sodium Channel Blockers

• Tetrodotoxin - Pufferfish ovaries

• Scorpion Toxin

• Batrachotoxin - South African frog

Potassium Channel Blocker Tetraethyl Ammonium (TEA)

Calcium Channel Blocker Cobalt

Question: How do we know that a voltage change across the membrane opens ion channels?

Answer: The Patch-Clamp Technique

Llinas, 1992 Visualized calcium entry into terminal bouton•Giant Squid axon•Inject bouton of axon with jelly fish protein•protein emits light when it binds with Ca++

Experiment a. Stimulate the axon to cause action potential b. Detected rapidly flicking spots of light in bouton at transmitter release sites

Transmitter-gated Voltage-gated Channels Channels

Transmitter binding to Na+ Channel opens receptor

Opens NA+ channel Additional Na+ inflow

Na+ inflow Depolarization reaches Threshold

Depolarization Action Potential

Two Different Systems of Neurochemical Transmission

Small molecule neurotransmitters• Synthesized in terminal bouton

• Short-lived effect on receptor

Large molecule neurotransmitters• Peptides (chains of amino acids)

• Synthesized in cell body

• Transported in vesicles to bouton

G-protein linked receptor

G- protein has a subunit (alpha subunit)

induces second messenger synthesis

Bind to ion

channel influence enter nucleus neuron metabolic activity gene expressionOpen or close

channelProtein synthesis

Transmitter - receptor Binding

Two General Receptor Types 1. Ion-channel linked receptor

- Ionotropic

2. G-protein linked receptor

- Metabotropic

Neurotransmitters Acetylcholine (ACh) Monoamines Epinephrine - adrenaline Norepinephrine - noradrenaline Dopamine Serotonin Amino acids Peptides Gases

Acetylcholine(ACh) - Soma locations 1. Spinal motor neurons Skeletal muscles

2. Septum Hippocampus

3. Nucleus Basalis Cortex 4. Vagus nerve Smooth muscles (internal motor neurons organs-e.g., heart)

5. Interneurons

Biosynthesis of AcetylcholineAcetyl coenzyme A (acetyl CoA)

Coenzyme A (CoA)

Choline

Acetylcholine

Choline Acetyltransferase (CAT)

enzyme

Acetate ion

Two Types of ACh Receptors

1. Muscarinic Receptor smooth muscles (e.g., heart) brain neurons G protein-linked or metabotropic receptor

muscarine = agonist atropine = antagonist

2. Nicotinic receptor skeletal muscles brain neurons ionotropic receptor nicotine = agonist curare = antagonist

Antagonists of ACh Transmission

1.Clostridium Botulinum - bacteria in poorly canned food - produces botulin neurotoxin - inhibits ACh release

2. Black Widow Spider Venom - venom = protein - binds with bouton membrane - forms a pore - CA++ enters the pore - depletes neurotransmitter

3. Cobra Venom - venom = protein - binds to nicotinic receptor - prevents ACh binding to receptor

4. Organophosphates - irreversible acetylcholinesterase (AChE) inhibitors - nerve gas - prevent breakdown of ACh - promotes receptor desensitization ion channels close despite high ACh levels

Myasthenia Gravis

• Autoimmune disease• antibodies against nicotinic ACh receptor• receptor number reduced• clinical symptoms

- muscle weakness (eyelids, limbs, respiration)• treatment

- physostigmine = AChE inhibitor

MonoaminesDopamineNorepinephrine Epinephrine

Tyrosine

L-Dopa

Dopamine

Norepinephrine

Epinephrine

-----------

-----------

Released from varicosities

Dopamine Soma locations Substantia Nigra

Ventral Tegmental Area (VTA) Receptors 5 subtypes (D1 - D5)

Norepinephrine Soma locations Locus coeruleus

Receptors Beta (B1. B2, B3) Alpha (A1, A2)

Epinephrine Soma locations Medulla

Serotonin (5-HT)

Tryptophan

5-hydroxytrytophan (5- HTP)

5-hydroxytryptamine (5- HT) (Serotonin)

Serotonin Soma locations Raphe nuclei

Receptors 15 subtypes

Amino Acids

1. Glutamic acid (glutamate) - main excitatory neurotransmitter

Soma locations - Everywhere Receptors 10 subtypes

Amino Acids - continued2.Gamma-aminobutyric acid(GABA) - main inhibitory neurotransmitter Soma locations - everywhere Receptors

two types

GABA A - Chloride channel Benzodiazepines -Valium

Librium GABA B

Neuropeptides Enkephalins Vasopressin Oxytocin Substance P Cholecystokinen Neurotensin Somatostatin Neuropeptide Y Vasoactive intestinal peptide Angiotensin Corticotropin-releasing factor Beta-endorphin

Soluble Gases

Nitric oxideCarbon monoxide - Do not bind to receptors - diffuse into neurons - activate second messengers