Glutamate and aspartate
Most common excitatory transmitters in the brain. Both appear to bind to the same receptors, and almost all study has focused on the actions of glutamate. There are several major classes of glutamate receptors, some of which are metabotropic (modulatory) while three of which are ionotropic, ligand-gated ion channels. Glutamate has one more CH2 than aspartate, but otherswise identical structures.
named after its preferred artificial agonis, N-methyl-D-aspartate. NMDA receptor forms a channel which is blocked at normal resting potentials by extracellular Mg2+ The block is only relieved by depolarization of the cell. To activate NMDA receptors, the cell must simultaneously be depolarized as the receptor blinds to glutamate. These receptors play important roles in simple forms of learning and memory and in development. NMDA-activated channels tend to open and close more slowly than other glutamate receptors (AMPA and Kainate receptors)
When both NMDA and AMPA receptors are present at a synapse:
rapid onset, slow offset epsp (excitatory postsynaptic potential).
GABA (y-aminobutryric acid) and glycine
Major inhibitory transmitters in the nervous system. GABA predominiates in brain, glycine in spinal cord. Inhibition mediated by GABA and glycine receptors plays a critical role in controlling ongoing excitation in the brain, as modulation of inhibition has very marked effects on consciousness.
Include valium and librium. Major drugs for the treatment of anxiety and as sleep aids. Act by binding to an allosteric binding site on the GABAa receptor and enhancing the inhibitory action of GABA.
Neurotoxin that acts as antagonist of glycine and acetylcholine receptors. Blocks inhibition of the spinal cord (since glycine is an inhibitory transmitter of the spinal cord), leading to convulsions and death. Ex: English murder mysteries
neurotransmitter of mammalian motorneurons and of parasynpathetic neurons. Quantitatively mionr role in the brain. Two classes of receptor: nicotinic and muscarinic. During inactivation step, acetylcholine is broekn down by an extracellular enzyme, acetylcholinesterase
Acetylcholine receptors. Ionotrophic (form an ion channel pore). Vertebrate neuromuscular junction receptors. Nicotine activates sympathetic neurons, causing dizziness, inceased heartbeat, and elevated blood pressure in new smokers. Nicotinic receptors are mostly localized on pre-synaptic terminals in the brain, enhancing transmitter release when they are active.
Acetylcholine receptors that are metabotropic (acts as a secondary messenger. indirectly linked with ion channels on the plasma membrane of the cell through signal transduction mechanisms, often G proteins), named after muscarine, a toxin from poisonous mushroom.
Catecholamines (dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline)
All derived from amino acid tyrosine in a series of steps. They are all trace transmitters in the brain
Dopamine and Norepinephrine
Play very important roles in awareness, emotional state, and consciousness.
Dopamine is found in many different discrete pathways and plays a role in a number of important behaviors, including reward systems, drug addiction, emotional state and psychiatric illness, cognitive function, and motor control. Death of dopaminergic neurons in substantia nigra leads to Parkinson’s disease
Synthesized by a tiny nucleus of neurons (the locus coeruleus) which sends projections diffusely throughout the brain. Thus, it is likely to play a general modulatory role rather than being involved in discrete information transfer. Activity in noradrenergic neurons increases markedly when an animal is presented with a novel stimulus. Norepinephrine often acts by a conductance decrease mechanism to enhance neuronoal excitability to both excitatory and inhibitory synaptic inputs
Trace transmitter in the nervous system, but a major circulating hormone in the blood. Associated with fight-or-flight responses. All of the catecholamine receptors are of the modulatory type(metabotropic)
small-molcule neurotransmitters: biogenic amines
catecholamins (dopamine, norepinehprine, epinephrine), indoleamine, imidazoleamine
an idoleamine. small-molecule neurotransmitter. synthesized from amino acid tryptophan. similar diffuse distribution in the brain to norepinephrine and also plays a general modulatory role. Has been implicated in may behaviors including sleep regulation and eaming appetite, thermoregulation, pain perception and analgesia, migraine, depression, and motor coordination. One of the serotonin receptor subtypes (5HT3) is an ionotropic receptor; the others are all modulatory metabotropic receptors
only serotonin receptor subtype that is ionotropic.
huge class with hundreds of members and more being discovered all the time. All are short stretches of amino acids cut from larger protein precursors.
family of peptides that interact with the same receptors as opiates such as heroin; they play a role in pain suppression and in reward
major transmitter for sensory neurons that are selective for painful stimuli
histamine, adenosine, ATP and octopamine, and unsusual retrogade compounds such as nitric oxide (NO), endocannabinoids, and arachidonic acid, which send signals backward from the post-synaptic neuron to the pre-synaptic terminal. These are nuumerically less common overall in the brain but play critical roles for specific behaviors and responses. The retrograde transmitters play unusual roles in modulation of synaptic strenth
life cycle of a neurotransmitter
1. synthesis: transmitter is synthesized from precursors. For all transmitters except the peptide, the synthetic enzymes are present in the pre-synaptic terminal, and they make the transmitter from precursors that are accumulated by a high affinity uptake mechanism that is localized to the nerve terminal.
2. packaging into vesicles: the synthesized compounds must be concentrated into vesicles before release can occur. For the small compounds, this appears to involve a pump that uses a pH gradient between the inside and outside of the vescicle as an energy source. This pH gradient is in turn set up by a proton ATPase which pumps protons into the vesicle at the expense of ATP.
4. binding to receptors – most drugs that act in the nervous system do so by interfering with receptor action.
5. inactivation – action of transmitters in synaptic cleft is terminated by several different mechanism.
Synthesis of peptides
Peptides are synthesized initially as high-molecular weight protein precursors, which are then cut into small pieces by endopeptidases. This primarily occurs in the cell body, as there are few ribosomes (and thus little protein synthesis) in the terminals. The peptides are then packaged in vesicles and shipped to terminals by rapid axonal transport. The consequence is that there is a limited supply of peptide in the nerve terminal at any time.
disease characterized by muscle weakness and reduction in transmitter release from the neuromuscular junction. Recent work has shown that this is an autoimmune disease, where the patients make antibodies against their own calcium channels. When their serum antibodies are tested in vitro, they block the voltage-sensitive calcium current in a number of cell types. Lambert-Eaton Syndrome demonstrates the requirement for calcium entry through voltage-sensitive channels.
cause of most cases of fatal food poisoning in the U.S. Contains a number of different proteases which specifically cleave proteins involved in transmitter release (syntaxin, SNAP-25, synaptobrevin), thus interfering directly with the fusion of vesicles. It kills by respiaratory paralysis as a consequence
Botulinum toxin. Injueted into specific muscles to block synaptic transmission and thus block muscle contraction that contributes to wrinkles
Extracellular enzyme that breaks down acetylcholine during inactivation step of neurotransmitter. Many nerve gases and insectiicides (such as organophosphates) act by blocking the acetylcholinesterase enzyme, thus overstimulating the cholinergic synapses (for example, the neuromuscular junction). The consequence is that the acetylcholine receptor shift into a new closed state, called the desensitized state, blocking transmission and killing by flaccid paralysis.
Inactivation step of amines and amino acids
Amines and amino acids are recycled by reuptake into the pre-synaptic terminal and repackaging into vescicles Specific transporter proteins mediate this update, and it is often dreiven by energy derived from the sodium gradient (sodium-transmitter cotrainsport).
Psychoactive drugs effect on transport
Several psychoactive drugs (such as cocaine and ecstasy) block specific transporters.
Not actively removed from cleft. Difffuse away and are broken down by nonspecific peptidases, which explains in part their very prolonged actions.
rapid receptiors which are also ion channels like the ACh receptor at the Neuromuscular junction
slow, modulatory receptors which activate second messenger mechanisms in the cell through interactions with the signal-transducing G proteins
Nicotinic ACh receptor
More is known about this receptor than any other. Completely purified from a number of sources. Muscle nAChR is made of 4 proteins in a 2:1:1:1 ratio. 2 α, 1 β1, 1 γ, and 1 δ subunit. The two alpha subunites each bind ACh and the competitive antagonists. Careful E.M. and X-ray diffraction studies show AChR to look like a donut with a central hole. The hole is the ion channel, formed from interactions between the protein subunits. The genes for all 4 submunits have been cloned and sequenced, and they show a considerable amount of homology, and have all evolved from a single ancestral gene.
Protein subunits of nicotinic ACh receptor
studies of relative hydrophobicity of stretches of the amino acids tin the sequences have developed models suggesting each subunite possesses 4 transmembrane spanning region. The central pore is thought to be lined by the M2 trans-membrane sequences from the different subunits.
Selectivity of nAChR for cations
The selectivity of the channel for cations over anions is thought to arise from three rings of negatively charged amino acids (glutamate and aspartate) that are found on both sides of the M2 trans-membrane domains. These negative charges form a barrier, repelling anions while attracting cations into the channel.
Using molecular genetic techniques, one can introduce mutations into the amino acid sequence at any desired site and test hypotehsis about twhat the different amino acids are doing. Example: confirmation of model for selectivity of nAChR for cations – when negatively charged amino acids ringin the pore are eleminated, the conductance of the channel decreases, supporting the model.
Other rapidly acting transmitter receptors
a nunmber of subunits for the neuronol nicotinic ACh receptor, glutamate, GABA and glycine receptors, and the ionotropic 5HT3 serotonin receptor have been cloned and amino acid sequences determined. All of these receptors except the glutamate receptors share considerable sequence homology, far more than could be expected by chance. Conclusion: these ligand gated ion channel receptor genes evolved form a single ancestral gene.
quite different from all the others. evolved independently as a separate ligand-gated ion channel family.
modulatory receptor supergene family
receptors are not ion channels at all, but large proteins that interact with G proteins to activate the biochemical cascade of intracellular events. They include alpha and beta adrenergic receptors (for epinephrine and norepinephrine), dopamine receptors,several muscarinic ACh receptors, a large familiy of serotonin receptors, and peptide receptors. HOMOLOGOUS in their sequences and have all evolved form a single gene which is different from AChR-related ancestral gene.
Modulatory receptor supergene family structure
each receptor shows 7 membrane-spanning regions and a large third cytoplasmic loop, which interacts with the G proten. A single protein subunit forms the functional receptor, in contrast to the multi-subunit transmitter receptors. A separate family of genes codes vfor the metabotropic glutamate receptors, again suggesting that glutamate transport pathway is evolved independently of other transmitters.
types of chemical synaptic transmission
1. synthesis and storage of a transmitter substance
2. release of the transmitter
3. interaction of the transmitter with receptors at the postsynaptic membrane
4. removal of the transmitter from the synaptic cleft
nerves stimulated by acetylecholine
nerves stimulated by epinephrine or norepinephrine
glutamate, aspartate, glycine
dopamine, norepinephrien, epinephrine, serotonin
enkaphalins, substance P, oxytocin, vasopressin
nicotinic acetylcholine receptor