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NEUROTRANSMITTERS/RECEPTORS I. NT Receptors A. Ionotropic Receptors: transmembrane proteins having an internal pore (ligand-gated ion channel) 1. Four TM domains a) nACh Receptors **FIGURE 6.3a/c**. b) GABAA & glycine Receptors 2. Three TM helices a) AMPA receptors (glutamate Rs) b) NMDA receptors (glutamate Rs) [subunit composition determines specific subtype properties, e.g. calcium-permeable vs calcium-impermeable NMDA receptors] **FIGURE 6.4a/b**. B. Metabotropic receptors 1. Seven TM regions 2. Shared NTs (with ionotropic Rs) but different outcomes: linked to intracellular pathways 3. G protein-coupled **FIGURE 6.5**. II. Classical Neurotransmitters A. Acetylcholine (ACh) 1. NT at the vertebrate NMJ 2. Rapid local synthesis: choline acetyltransferase (ChAT); defines a cholinergic neuron 3. Excess: desensitization of receptor **FIGURE 6.2**.
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B. Amino Acid NTs: 1. Glutamate: from glutamine; rapidly recycled via transporters 2. -Amino butyric acid (GABA): from glutamate by glutamic acid decarboxylase (GAD) 3. Others: aspartate, glycine **FIGURE 6.6** **FIGURE 6.8**.
C. Biogenic Amines: 1. From tyrosine: dopamine, norepinephrine, epinephrine (catecholamines) 2. From tryptophan: serotonin (5-Hydroxytrypamine) **FIGURE 6.1**. D. Other: Purines (e.g. ATP)
IV. Non-classical transmitters A. Neuropeptides 1. Multi-step synthesis: pre-proproteins (RER) to pro-peptides in vesicles and then to peptides 2. Delivery: transported to axon terminals, released, cleaved (not recycled).
**FIGURE 6.14**. B. Retrograde Transmitters 1. Endocannabinoids see previously paper (Wilson & Nicoll, 2001). 2. Nitric oxide (NO): released from arginine; diffuses across
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membrane; can act retrograde across synapse **FIGURE 6.18**. V. Interesting NT Receptor subtypes A. AMPA vs NMDA glutamate receptors 1. AMPA Rs requires only glutamate for activation; rapid on/off 2. NMDA Rs requires glutamate, glycine, & membrane depolarization (to relieve Mg++ block), thus needing convergence of events. **FIGURE 6.7a-c**. B. GABAA receptors Chloride multiple permeable; regulation sites **FIGURE 6.9a/b**.
VI. Original Reference - Liu Z, Neff RA, Berg DK (2006) Sequential interplay of
nicotinic and GABAergic signaling guides neuronal development. Science 314:1610-1613.
A. Background: GABA, the main inhibitory transmitter in the brain, is actually
excitatory during embryogeneis and early postnatal life because of a reversed Cl- gradient. The excitatory phase of GABA signaling is critical for proper neuronal development and integration into circuits, i.e. synapses forming onto the neuron. Key to the GABA switch from excitation to inhibition is the appearance of the mature Cl- transporter KCC2, which pumps Cl- out of the cell, and the loss of the immature transporter NKCC1, which pumps Cl- into the cell. The mature Cl- gradient then enables GABA to be inhibitory (Cl- rushes in when GABAA receptors are activated).
B. Experiment: Spontaneous nicotinic cholinergic signaling drives waves of
excitation through the embryonic and early postnatal nervous system. Might this be related to the GABAergic switch? Test whether blocking nicotinic activity delays the developmental conversion of GABAergic transmission from excitation to inhibition. Methods: (1) In chick embryos block nicotinic activity receptor antagonists. (2) In mice block nicotinic activity by removing nicotinic receptor
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genes (knockouts). Easy test for GABA excitation: calcium fluor to report calcium influx (through VGCCs opened by the GABA excitation).
C. Results: Endogenous nicotinic activity determines when GABAergic signaling
converts from excitation to inhibition. Nicotinic activity does this by increasing KCC2 and decreasing NKCC1 to make a mature chloride gradient. Also shown (in other figures): (1) Preventing the depolarizing phase of GABA signaling causes the neurons to get less innervation. (2) Interestingly, even the initial inhibitory phase of GABAergic signaling has developmental instructions if, and only if, the neurons is also getting nicotinic excitation (integration is key).
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**Fig. 1 from Liu et al., 2006** **Fig. 2 from Liu et al., 2006**