Receptors & Transmitters DENT/OBHS 131 Neuroscience 2009

Learning Objectives Know what criteria are used to define a neurotransmitter Recall the major different categories of transmitters Know the names of the principle neurotransmitters in the CNS (including: glutamate, GABA, acetylcholine, norepinephrine, serotonin and dopamine) Compare and contrast small the synthesis and action of small molecular weight and peptide transmitters Identify the brainstem nuclei associated with the biogenic amine transmitters Compare and contrast ligand-gated and G-protein coupled receptors

You are a neurotransmitter if you…. are produced within a neuron, and are present in the presynaptic terminal are released during depolarization (action potential-dependent manner) act on receptors to cause a biological effect have a mechanism of termination

More strictly, to be a transmitter.. a particular substance, when applied to the post- synaptic cell in quantities equal to that released by the pre-synaptic cell, produces the same post-synaptic response as does a pre-synaptic action potential

Learning Objective #2 & 3 Recall the major different categories of transmitters Know the names of the principle neurotransmitters in the CNS (including: glutamate, GABA, acetylcholine, norepinephrine, serotonin and dopamine)

The keys Small molecular weight: Acetylcholine (ACh) Amino acids: Glutamate, GABA, glycine Biogenic amines: Catecholamines: Dopamine, Norepinephrine (Epinephrine) Indolamines: Serotonin (5-HT), Histamine Nucleotides ATP, Adenosine

More keys... Neuropeptides Unconventional (what?) (yes, I want to be a transmitter but I’m not going to tell you exactly how)

Learning Objective #4 Compare and contrast small the synthesis and action of small molecular weight and peptide transmitters

Small Molecules

Neuropeptides

Back to transmission…..

Where are the transmitters?

Amino Acids Glutamate everywhere in CNS major excitatory transmitter in CNS most projection neurons in cortex use glutamate GABA everywhere in CNS major inhibitory transmitter in CNS found (not always) in local circuit neurons (interneurons) Glycine major inhibitory transmitter in brainstem and spinal cord

L -Glutamate

Synthesis and Degradation: GABA Kreb’s Cycle  -ketoglutarate glutamate GABA (release & uptake) The GABA Shunt glutamic acid decarboxylase (GAD) succinic semialdehyde succinic acid

Distribution: Acetylcholine 5% Ventral horn spinal motor neurons (PNS) to skeletal muscle Brain stem motor nuclei Striatum (local) Septal nuclei to hippocampus Nucleus basalis to cortex, amygdala, thalamus PNS - autonomic Cognition - memory Motor (striatum)

Learning Objective #5 Identify the brainstem nuclei associated with the biogenic amine transmitters

Locus coeruleus to everywhere attention, alertness circadian rhythms memory formation mood Distribution: Norepinephrine (NE) 1%

Rostral raphe nuclei to nearly all regions of the brain Caudal raphe nuclei to spinal cord mood sleep / wake cycles pain modulation Distribution: serotonin (5-HT) 1%

Substantia nigra to striatum Ventral tegmentum to: Amygdala, nucleus Accumbens & prefrontal cortex Arcuate nucleus to median eminence of hypothalamus movement motivation sex hormones Distribution: Dopamine 3%

DopamineTyrosine L-DOPA tyrosine hydroxylase dopa decarboxylase HO CH 2 -CH-NH 3 COOH + HO CH 2 -CH-NH 3 COOH OHOH + HO OHOH CH 2 -CH-NH 3 H + (these steps occur within the cytoplasm) Synthesis: Dopamine

dopamine-  -hydroxylase (DBH) Dopamine Norepinephrine HO OHOH CH 2 -CH-NH 3 H + HO OHOH CH-CH 2 -NH 3 OH + (these steps occur within the synaptic vesicle) Synthesis: Norepinephrine

Transmitter termination Clinical relevance: Neurotransmitter transporters: MAOs: disease (epilepsy, ALS, Parkinson’s) drug abuse (cocaine, amphetamine) treatment (depression, OCD)

Learning Objective #6 Compare and contrast ligand-gated and G-protein coupled receptors

Classes of Neurotransmitter Receptors Ionotropic Receptors Ligand-gated ion channels Fast synaptic transmission (1 ms) Are closed (impermeable to ions) in absence of transmitter Neurotransmitter binding opens receptor (direct) Metabotropic Receptors G-protein coupled receptors (GPCRs) Slow onset and longer duration of effects (100 ms & longer) Ligand binding activates GTP-binding proteins (indirect)

Ligand-gated / G-protein Coupled

Transmitter and receptor pairing Both ionotropic and metabotropic receptors: glutamate acetylcholine GABA 5HT (serotonin) Just ionotropic: glycine Just metabotropic: other biogenic amines (DA & NE)

Each subunit has multiple membrane spanning domains Glutamate: 3 All others: 4 Multimers Glutamate: 4 All others: 5 Glutamate Receptor SubunitsAll Other Receptor Subunits Ligand-gated ion channels

Allosteric “other” binding sites

Congenital myasthenia Single channel lifetime shortened open slower & close faster (Wang et al, 1999)

Structure of G-protein Coupled Receptors Single polypeptide with 7 TM domains (no subunits) 2nd & 3rd cytoplasmic loops plus part of the intracellular tail bind to appropriate G protein

Agonist binding causes conformational change that activates the G-protein cholera toxin pertussis toxin

Direct modulation of Ca 2+ channels

Modulation Through 2 nd Messenger Pathway

“Retro” transmitters NO endocannanbinoids

Definitions… Agonist = activates (opens) the receptor when it binds Antagonist = binds to the receptor and inhibits its function different types Allosteric modulators = act at a site different from agonist Desensitization = response decrease although the agonist is still present or repetitively applied Ligand gated ion channels: Gating = opening / closing of the channel Kinetics = how long processes take Affinity = tightness of the agonist binding Efficacy = how readily the channel opens