Properties of Receptors

A. Characteristics of receptors

1. Receptors must show saturability. Must be finite population. If not saturated, probably non-specific.

2. Sensitivity: Many drugs produce marked effects at low doses. The drug-receptor combination requires amplification to induce a response. This is provided by a cascade of amplification steps.

3. Selectivity: Responses involving any given type of receptor are only elicited by a fairly narrow range of chemical substrates with similar structural groupings and electronic properties.
   1. Divergence from the optimal structure (optical isomers) may result in complete loss of activity.
   2. Selectivity is greater with agonists than antagonists.

4. Specificity. The response of cells in any given type of agonists acting on the same set of receptors is always of the same type (determined by the properties of cells). Has to show binding to preferred chemicals.

5. Reversibility: All drugs are expected to be found in bound or unbound state.

6. Restoration of function on reconstitution: Must work after you put them back together again.

   * Never assume that receptors are fixed and stable. Can change affinity or receptor number.

B. Many types of receptors for each neurotransmitter

C. Needs for Receptor Action

1. The drug-receptor interaction must proceed with sufficient stability to initiate the effect

2. However, most drug-receptor interactions are reversible

3. Different rates of association and dissociation

4. Binding is a concerted effort of three forces:
   1. Ionic Bond: Must overcome random thermal agitation of drug to draw it to receptor
   2. Hydrogen Bonds & Van der waals Forces: Combine to stabilize the drug-receptor complex
   3. Electrostatic attraction
   4. Drug sits on receptor, then ionic bond holds it there. Hydrogen bonds and Vander Waals Forces lock it into position.

Cellular Foundations

A. Forces across membrane.

1. Diffusion Force: Identical particles move apart form high concentration to low.

2. Semi-permeability: Membrane allows some ions to pass while preventing others. K+ flows more easily than Na+.

3. Electrostatic repulsion: Like forces repel.

4. Na+ - K+ Pump: Exchanges intracellular Na+ for extracellular K+.

B. Factors that influence neurotransmitter release

1. Transport of neurotransmitter down axon.

2. Electrically excite pre-synaptic membrane.

3. Organelles in nerve terminal synthesize or store neurotransmitter.

4. Extracellular space: enzymes and glial cells break down and release neurotransmitter.

5. Post-synaptic receptors channel opening and closing.

6. Organelles in postsynaptic cell. alter synthesis to activity.

7. Genetic expression. May alter rate at which post-synaptic cells produces more receptors. Dictates protein synthesis.

8. Plastic step. contact zones. Change in function. Some cells co-release neuromodulator with neurotransmitter.

9. Post-synaptic membrane receptive to signals - electrically active.

10. Propagation down axon.

11. Axo-axonic synapse mediates pre-synaptic inhibition.

12. Autoreceptors (in pre-synaptic receptors) participate in feedback regarding production and release of neurotransmitter.

Characteristics of Neurotransmitters (NT)

A. Characteristics of neurotransmitters

1. Must be synthesized in a neuron
2. Must be present in axon terminal
3. Released in response to stimulation
4. When applied exogenously, get a biological effect
5. There is some mechanism for removing them from synaptic cleft.

B. Methods of studying Neurotransmitters

1. Radio-isotopic method: Inject radioactive chemical. Measure synthesis and metabolism.

2. HPLCEC: dissect tissue and add HPLC - records metabolism.

3. Microdialysis: (in vivo). Inject probe to neuron. Fill tube with CSF. collect fluid. Purpose is for studying release.

4. Histochemical fluorescence microscopy: Freeze dried tissue exposed to formaldehyde gas. Highlights NT as fluorescent under ultraviolet light.

5. Neurotoxins: Synthesized by chemists - specific to one NT receptor. Absorbed by neurons. Metabolized to a toxic state in the neuron to cause cell death. Lose one NT system.

C. Stored in vesicles. Properties of vesicles:

1. Have membrane
2. Have high concentration of NT. Will sometimes store enzymes too.
3. Sequester NT. Protect NT from being broken down.
4. Brings NT back into presynaptic cells. Involved in reuptake.
5. Drugs like reserpine affect membrane of vesicles.

D. Release

1. Arrival of action potential in nerve terminal
2. Calcium channels open. Calcium influx at nerve terminal.
3. Exocytosis

Transmitter Substances

A. Acetylcholine

1. The effect that a transmitter substance has on the postsynaptic membrane is not determined by the chemical itself but by the nature of the postsynaptic receptors it stimulates.
   1. Excitatory effect on skeletal muscles. Control sodium ion channels and produces depolarizations.
   2. Inhibitory effect on the muscle fibers of the heart. Controls potassium ion channesl and produces hyperpolarizations.
   3. Also plays role in learning and remembering and controls the onset of REM sleep.

2. Deactivation.
   1. Acetylcholine is the only neurotransmitter destroyed in the synapse--by the enzyme acetylcholinesterase (AChE) in the synapse
   2. AChE is also present in the cytoplasm to destroy any transmitter substance produced by the cell that exceeds the storage capacity of the synaptic vesicles.

3. Two different types of acetylcholine receptors
   1. Nicotinic (named after nicotine--a poison found in tobacco leaves)
      1. Muscle fibers contain only nicotinic receptors.
   2. Muscarinic (named after muscarine--a poison found in certain mushrooms).
      1. The CNS contains mostly muscarinic receptors, but also some nicotinic receptors.

B. The Monoamines

There are four drugs considered monoamines because their molecular structure is similar. Because these are so similar, some drugs will affect each of these receptors to a degree. Within the mammalian central nervous system, there is evidence that the monoamine transmitters are found in pathways essential for sensory and motor performance as well as for higher brain functions. However, out of the total cells in the human brain, relatively few appear to contain these transmitters-thousands rather than millions or billions. What is more, most of the cells containing these transmitters are clustered together in discrete regions of the brain.

Three of the monoamine neurotransmitters are classified in a subclass, catecholamines. These are epinephrine, norepinephrine, and dopamine. Most neurons that release catecholamines do not do so through terminal buttons on the ends of axonal branches. Instead, they usually release them through axonal varicosities, beadlike swellings of the axonal branches. These varicosities give the axonal branches the appearance of beaded chains.

The Catecholamines

1. Dopamine
   1. Dopamine produces excitatory or inhibitory postsynaptic potentials, depending on the postsynaptic receptor.
   2. Most dopamine is produced and secreted by the Substantia Nigra.
      1. Degeneration of the Substantia Nigra causes Parkinson's Disease, a movement disorder characterized by tremors, rigidity of the limbs, poor balance, and difficulty in initiating movement. The cell bodies of the neurons that produce dopamine are located in the Substantia Nigra. People with Parkinson's disease are given L-Dopa, a drug that stimulates the production of dopamine, thus causing more dopamine to be released by the surviving dopaminergic neurons.
   3. Role of dopamine
      1. Involved in controlling or initiating movement
      2. Regulation of mood. Imbalances of dopamine have been associated with disorders such as schizophrenia or depression.

2. Norepinephrine
   1. Also known as noradrenaline
   2. Produced from Dopamine in the cytoplasm of the terminal button and stored in synaptic vesicles.
   3. Role of Norepinephrine
      1. In the brain, norepinephrine is released by the Locus Coeruleus, and has an inhibitory effect. It is believed that in the CNS, norepinephrine is primarily involved in control of alertness and wakefulness.
      2. In the sympathetic nervous system norepinephrine has an excitatory effect. Released by nerves in internal organs, including the gut, spleen, and heart.
      3. Regulation of mood. May be responsible for some symptoms of depression.

3. Epinephrine
   1. Also known as adrenaline
   2. Synthesized from norepinephrine in the adrenal medulla, the central core of the adrenal glands.
   3. Role of Epinephrine
      1. In the brain, the role is not entirely known, but it is believed to play a role in the way the brain regulates blood pressure.
      2. In the periphery, it is the main circulating exciting transmitter released during the "fight or flight" stress reactions.
      * It is important to note that most of the receptors sensitive to norepinephine are also sensitive to epinephrine. All of these receptors are coupled to G proteins that generate the second messenger cyclic AMP.

The Indolamines

1. Serotonin
   1. Sometimes referred to by its chemical composition, 5-hydroxytryptamine (5-HT).
   2. Differs from catecholamines in having, in addition to the catechole ring, an indole ring. This is why it is called an indolamine rather than a catecholamine.
   3. Synthesized and released by a cluster of cells in the raphe nuclei in the brain.
   4. Role of Serotonin
      1. Mostly inhibitory effects on the post-synaptic membrane
      2. Involved in the control of eating, control of sleep and arousal, and in the regulation of pain.
      3. Regulation of mood. Certain anti-depressant drugs keep Serotonin prevent the normal reuptake of Serotonin to keep it in the synapse longer.
      4. Control of dreaming. (Suppresses REM sleep).
      * LSD acts at Serotonin receptors. LSD produces dreaming while the person is awake.

Amino Acid Transmitter Substances

Amino acid transmitters are located in the brain in far greater quantities than neurotransmitters. Because amino acids are used for protein synthesis by all cells of the brain, it is difficult to prove that a particular amino acid is a transmitter substance. Eight amino acids have been discovered to serve as transmitters, but we will only discuss three of them.

A. Glutamic acid

1. Principle excitatory transmitter substance in the brain.
2. Appears to play a role in learning and memory.
   * MSG (monosodium glutamate), a preservative found in many oriental foods, activates some glutamic acid receptors and may cause dizziness and numbness.

B. GABA (Gamma amino butyric acid)

1. Inhibitory transmitter that has widespread distribution throughout the brain and spinal cord. Inhibitory neurons are necessary for stabilizing the electrical activity.
2. One type of GABA receptor opens the chloride ion channels and another type opens potassium channels.
   * Certain drugs, such as barbituates or alcohol, can enhance the inhibitory effects of GABA.

C. Glycine

1. Inhibitory transmitter in the spinal cord and lower portions of the brain.
2. Little is known about this transmitter, but if glycine synapses are blocked (like with the bacteria that causes Tetanus), we would see continuous contraction (like lock-jaw).

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