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Agonist

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Any ligand (including NT's) that binds to a receptor and produces a physiological effect. Can be Partial or Inverse

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Partial Agonist

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Binds to the same site as a Full Agonist but has a lower physiological efficacy at an equimolar concentration of the Full Agonist

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Inverse Agonist

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Has an action opposite that of the Agonist

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Antagonist

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Blockers of the actions of the Agonist Competitive and Non-Competitive

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Competitive Antagonist

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Binds to the agonist's binding site and can displace the agonist but has NO PHYSIOLOGICAL EFFECTS.

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Non-Competitive Antagonist

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Blocks the actions of the agonist, but does so at a site other than the Agonist's binding site. Does not include Ion Channel blockers, as they do not bind to any receptor, but simply lodge in the channel

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Allosteric Modulators

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Substances that act at regulatory sites somewhere on the receptor different from that of the Endogenous ligand. Their effects can be enhancing or inhibiting when compared to the Endogenous Ligand or other Agonists, and they typically function by causing conformational changes in the bound molecule.

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Benzodiazepine (BZD)

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Allosteric Modulator that binds to the GABA(a) receptor and enhances the channels conductance whenever GABA molecules actually become bound to their sites

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Choline Acetyltransferase (ChAT)

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Catalyzes the synthesis of Acetylcholine: AcetylCoA + Choline --> Acetylcholine

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Acetylcholinesterase (AChE)

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ACh is taken back up after exerting its effect, so it must be degraded by AChE: Acetylcholine --> Acetate + Choline

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Organophosphates

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Irreversible Cholinesterase inhibitors effective in very low concentrations, giving them some applications: Insecticides - Toxic to target but not animals and humans Nerve Poisons (Sarin, VS)

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Effects of Cholinergic Stimulation and Antidote

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EFFECTS: Vasodilation, Slower Heart Rate, Constriction of Bronchioles, Reduced Mucus Secretion in Respiratory Tract, Intestinal Cramps, Secretion of Saliva, Sweat and Tears, Miosis, Convulsions, Asphyxia and Death ANTIDOTE: Cholinergic Synaptic Blockers (Atropine)

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Pralidoxime (2-PAM)

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Directly acting antidote that couples to the bound toxin and facilitates hydrolysis of the bond at the esoteric site Serine residue on AChE.

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Biosynthesis of ACh

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AcetylCoA is readily available in Axon Terminal. Choline is taken up by transporters in Synaptic Areas (it is a degradation produce from AChE hydrolysis) ChAT produces ACh which is then taken up by vesicles.

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Nicotinic Receptor - Agonist, Antagonist, Type & Action

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AGONIST: Nicotine ANTAGONIST: Curare RECEPTOR TYPE: Ligand-Gated Ion Channel RECEPTOR ACTION: fEPSP Found at NMJ

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Myasthenia Gravis

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Autoimmune disease against Nicotinic Receptors at the NMJ

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Muscarinic Receptor - Agonist, Antagonist, Type & Action

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AGONIST: Muscarine ANTAGONIST: Atropine RECEPTOR TYPE: G-Protein Coupled (Gi, Gp) RECEPTOR ACTION: Can be sEPSP, or sIPSP Predominant Cholinergic Receptor in the CNS

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m1, m3, m5 Muscarinic Receptors

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↑ Phosophlipase C Activity via Gp: PIP₂ → DAG + IP₃ ↑DAG = ↑PKC ↑IP₃ = ↑ Ca²⁺ release from ER These receptors are associated with EPSPs!

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m2, m4 Muscaranic Receptors (Brain vs. Heart)

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BRAIN: ↓ Adenylate Cyclase via Gi: ↓ Adenylate Cyclase = ↓ cAMP HEART - Two different effects combine to reduce Heart Rate: BETA/GAMMA SUBUNITS: Open K⁺ channels, causing a hyperpolarizing effect. Gi/ALPHA SUBUNIT: Decreases Adenylate Cyclase, which reduces cAMP production and PKA function, acting to decrease conductance of Ca²⁺ channels *In the Heart, it is the m2 channel only that is functioning* m2,m4 channels are associated with IPSP's!

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Catecholamine Structural Differences

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Have the general structure: Catechol - CH(R1)-CH₂-NH₂(R2) DOPAMINE: R1 & R2 = H NOREPINEPHRINE: R1 = OH, R2 = H EPINEPHRINE: R1 = OH, R2 = CH₃

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Indoleamine Structures

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Indole-CH₂-CH₂-NH₂(R1) SEROTONIN: R1 = H with a 5-H on the Phenyl Ring ???

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Mapping Pathways of Brain

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Formaldehyde + Catecholamine = Green Fluorescence Formaldehyde + Serotonin = Yellow Fluorescence

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Enzymes of Catecholamine Synthesis

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1. Tyrosine Hydroxylase 2. DOPA Decarboxylase 3. DOPA β-Hydroxylase 4. Phenylethanolamine-N-methyltransferase

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Tyrosine Hydroxylase

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Cytoplasmic enzyme that catalyzes the RATE-LIMITING STEP: Tyrosine + O₂ → 1-DOPA REQUIRES: O₂, Fe²⁺ and a Pteridine Cofactor REGULATION: End Product Inhibition, Ca²⁺, Phosphorylation in response to cAMP

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DOPA Decarboxylase (1-Aromatic Amino Acid Decarboxylase)

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1-DOPA → Dopamine + CO₂ Alternative name for the enzyme is because it can accept a variety of substrates; also functions in Serotonin synthesis

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1-DOPA

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When given with a PERIPHERAL DOPA DECARBOXYLASE INHIBITOR it is a therapy for Parkinson's

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DOPA β-Hydroxylase

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Dopamine + O₂ --> Norepinephrine Enzyme contains Cu²⁺ and is found in Synpatic Granules

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Phenylethanolamine-N-Methyltransferase

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Cytoplasmic enzyme that catayzles the reaction: Norepinephrine + S-Adenosylmethionine → Epinephrine

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Location of Catecholamine Synthesis

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Adrenal Medulla

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Inactivation of Catecholamines

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Following action, they are taken back up via specific transporters into the Presynaptic or Postsynaptic Neurons. They can then either be packaged into vesicles and protected from degradation, or degraded.

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Monoamine Oxidase (MAO)

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Catalyzes first step in Catecholamine Degredation. Two isoforms: MAO-A and MAO-B.

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MAO-A vs. MAO-B

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A: Can degrade all three types of Catecholamines, but mainly E and NE B: Can degrade Dopamine

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Main Points of Catecholamine Degradation

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The degradation of all three Catecholamines is similar in that it is a three step process catalyzed first by MAO, then an Aldehyde Reductase/Dehydrogenase, and finally, COMT.

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Catechol-O-Methyltransferase (COMT)

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Requires Mg²⁺; catalyzes many reactions: It can degrade the intermediate products of Catecholamine Degradation AS WELL AS the beginning substrates (Dopamine, Epinephrine, Norepinephrine)

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Which Breakdown Products Can be Tested for in the Lab?

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The final breakdown products for NE and E are Methoxyhydroxyphenylglycol (MHPG) and Vanillylmandelic Acid (VMA). The final breakdown product for Dopamine is Homovanillic Acid (HVA). These breakdown products can be tested for in the lab.

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Catecholamine Pharmacology

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Excess Catecholamine = Behavioral Excitation; as a result, agents that elevate Catecholamines are useful in treatment of depression. Lack of Catecholamine = Depression; blocking Catecholamine function is used to treat Schizophrenia

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Dopamine and Cocaine

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Having similar structures, Cocaine is able to block the Dopamine transporter (DAT) on the Pre-synaptic Terminal, resulting in the accumulation of Dopamine in the synapse over time. The elevated Dopamine may be degraded by COMT, depending on the Brain Area

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Dopamine and Amphetamines

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Having similar structures, Amphetamines including METH and MDMA are able to enter Pre-synpatic Neurons and reverse the functioning of Dopamine Transporters. Dopamine in vesicles is released into the cytoplasm and cytoplasmic Dopamine is then pumped into the synapse. If MDMA is taken with a MAO inhibitor, the resulting Sympathetic effects can be lethal

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Enzymes of Serotonin Synthesis

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1. Tryptophan Hydroxylase 2. 5-Hydroxytryptophan Decarboxylase

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Tryptophan Hydroxylase

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Tryptophan + O₂ → 5-Hydroxytryptophan

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5-Hydroxytryptophan Decarboxylase (1-Aromatic Amino Acid Decarboxylase)

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5-Hydroxytryptophan → Serotonin + CO₂ Requires Pyridoxal Phosphate Same enzyme used in Catecholamine Synthesis

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Degredation of Serotonin

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Broken down by MAO-A into 5-HIAA which is excreted into urine

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Functions of Serotonin

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Regulation of Sleep and Wakefulness, Pain and Antinoceceptive Spinal Pathways

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Selective Serotonin Reuptake Inhibitiors (SSRI's)

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Antidepressants

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Glutamic Acid Decarboxylase

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Glutamate → GABA

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GABA Degredation

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GABA → Succinic Semi-Aldehyde → Succinic Acid

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GABA-T (GABA Transaminase)

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Two Reactions: α-Ketoglutarate → Glutamate GABA → Succinic Semi-Aldehyde

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Succinic Semialdehyde Dehydrogenase (SSADH)

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Succinic Semi-Aldehyde → Succinic Acid

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The GABA Shunt

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To produce GABA, you must pull α-Ketoglutarate out of the TCA cycle and not give it back until Succinic Acid is formed. The loss is 1 ATP (25% energy reduction for neurons): Kreb's Cycle = 3 ATP (from NADH) + 1 GTP (ATP) GABA Shunt = 3 ATP

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GABA(a) Receptors

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Fast Ionotropic Receptors that open Cl⁻ Channels causing Hyperpolarization of the cell Barbituates (Ethanol), Benzodiazepines, Steroids and Picrotoxins can also bind here

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GABA(b) Receptors

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Metabotropic Receptors connected to K⁺ channels through G proteins

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GABA(c)

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Slow Ionotropic Receptors that open Cl⁻ channels (Hyperpolarization) but have an insensitivity to some antagonists and regulators that affect the A subtype

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Serine Hydroxymethyltransferase

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Serine + THF → Glycine + N5-N10-Methylene THF + H₂O Produces Glycine, therefore, Glycine is not essential.

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Bicuculline

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Blocks GABA(a) receptors

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Strychnine

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Blocks Glycine Receptors

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Location and Function of Glycine Receptors

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LOCATION: Presynaptic Nerve Endings (Renshaw Cells, a type of Interneuron?) within the Spinal Cord FUNCTION: Released in response to high Ca²⁺, it opens ligand-gated Cl⁻ channels (Hyperpolarizing, IPSP)

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Glutamate and Receptor Types

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Glutamate is an excitatory Amino Acid NT in the CNS RECEPTOR SUBTYPES: Ionotropic: AMPA, Kainate, NMDA Metabotropic: mGluR1 - mGluR5

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NMDA Receptor

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Ionotropic Receptor activated by Glutamate that allows flows of Ca²⁺ as well as Na⁺ and K⁺ At resting potential, the voltage gradient pulls Mg²⁺ into the pore, occluding ion flow .If Glutamate is released at this point, it can bind to the receptor but will have no effect. Following Depolarizations, Mg²⁺ is ejected and the pore is opened. The receptor is also subject to regulation by Glycine, just FYI...........................................

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AMPA/Kainic Receptors

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Ionotropic Receptors activated by Glutamate that function in Na⁺/K⁺ conductance

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Long-Term Potentiation

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A synaptic mechanism involved in memory formation and associative learning which has been best characterized in the Hippocampus. Intracellular Ca²⁺ increases via NMDA receptors, leading to increased action by CaMK. The end result in increased numbers of AMPA receptors in the Postsynaptic Membrane and Activation of Transcription FActors such as CREB that modify synaptic structure. The end result is increased synaptic strength, meaning that the same Action Potential can produce greater EPSPs.

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