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I recommend reading the Summary (at the end) first.
Estimated study time: 2 hours.
CHEMICAL TRANSMISSION OF SYNAPTIC ACTIVITY
The process of transmission at a synapse comprises of the following steps:
- Synthesis (Of neurotransmitter in the nerve terminal)
- Storage (In synaptic vesicles)
- Release (Into the synaptic cleft, as a consequence of an action potential)
- Diffusion Away (Away from the synaptic cleft)
- Reuptake (of synaptic transmitter)
- Enzymatic Degradation
Neuromodulators = Chemicals released by neurons that influence the effect of neurotransmitters.
The action of a chemical mediator on its target structure is more dependent on the type of receptor on which it acts than on the properties of the mediator per se.
A few important principles to remember about receptors and mediators:
- Each chemical mediator has the potential to act on many subtypes of receptors(At least the ones studied)
- There are receptors on the presynaptic as well as postsynaptic elements for many secreted transmitters. They have to different functions
- Inhibitory – Inhibit the release of transmitter
Autoreceptors(inhibit further secretion of inhibitor, e.g. norepinephrine acts on Alpha-2 receptors to inhibit additional norepinephrine receptors)
Heteroreceptors(a receptor whose ligand is a chemical other than the transmitter released by the presynaptic neuron, e.g. norepinephrine acts on a cholinergic heteroreceptor to block the release of ACh).
- Stimulatory – Facilitate the release of transmitter.
- Inhibitory – Inhibit the release of transmitter
- Receptors belong to either one of the following two groups:
- Ligand-gated channels (ionotropic receptors)
- Metabotropic receptors (G-Protein coupled receptors)*I will talk about this type of receptors at a different time. I will insert the link here when I am done.*
- Receptors are concentrated in clusters on the postsynaptic membrane close to the endings of neurons that secrete the neurotransmitter specific to them.
- In response to prolongued exposure to ligands, most receptors become unresponsive, i.e. (lat. “id est” = eng. “that is to say)” they undergo desensitization.
There are two types of desensitization:
- Homologous desensitization = Loss of responsiveness of one particular type of receptor to its transmitter
- Heterologous = The cell becomes unresponsive to other ligands as well.
- Involves a high-affinity, Na+ dependent membrane transporter
- A transporter – the vesicular monoamine transporter(VMAT), in case of norepinephrine – places the molecules of transmitter into synaptic vesicles.
There are similar vesicular transporters for other small-molec. neurotransmitters.
Reuptake is relevant in clinlical practice, e.g. depression or glutamate poisoning.
Are of two types depending on the size and type of molecule:
- Small Molecule Transmitters (Amin-acids, ACh, and ATP) and
- Large Molecule Transmitters (Neuropeptides)
EXCITATORY AND INHIBITORY A.A.
– Main excitatory transmitter in the brain and spinal cord.
– Can be obtain via two(2) pathways, from either Alpha-Ketoglutarate (From Kreb’s cycle) or from Glutamine (Diffuses from glia, into the neuron where it is converted to Glutamate).
– Glutamate is also recycled from the synaptic cleft by glutamate transporters and then concentrated into synaptic vesicles by vesicular glutamate transporter.
Receptors for Glu:
Ligand-gated(ionotropic), named after their agonists:
- AMPA(Alpha-amino-3-hydroxy-5-methyllisoxazone-4-propionate) Present on all neurons of CNS, and also on glia.
- kainate(acid isolated from seaweed). Located presynaptically on GABA-secreting nerve endings and postsynaptically at various sites (notably Hippocampus, cerebellum and spinal cord.) Also found on glia.
- NMDA(N-Methyl-D-Aspartate). Present on all neurons of CNS. Requires Glycine to function (See picture below)Ionotropic receptors for Glu are tetrameres composed of different subunits. AMPA- 4, kainate- 5, NMDA- 6.Effects:
Glu + AMPA, or kainate = Influx of Na+ and efflux of K+, accounting for a fast EPSP.Glu + NMDA = Influx of Ca2+(Calcium) and Na+
This NMDA Channel is usually blocked by extracellular Mg2+ at normal membrane potentials. It is only activated when an action potential causes the activation of AMPA and kainate receptors.
- Located in both presynaptic and postsynaptic sites throughout the brain.
- Produce synaptic plasticity (particularly in hippocampus and cerebellum).
- Activation of presynaptic mGluR autoreceptors in hippocampus limits the release of glutamate in these neurons.
- Glu + mGluR = Intracellular – Increase of IP3 (Inositol-1,4,5-Triphosphate) and DAG (Diacylglycerol), or a decrease in cAMP.
GABA(Gamma-Amino Butyric Acid)
– Formed in the body by decarboxylation of glutamate, by the enzyme GAD(Glu Decarboxylase) which is present in nerve endings.
– Metabolized by transamination to succinic semialdehyde and then to succinate in the CAC.
In addition there is active reuptake of GABA via the GABA transporter and concentrated into synaptic vesicles by vesicular GABA transporter(VGAT)
Receptors for GABA:
There are three subtypes:
- In the CNS
- GABA-A – ionotropic
- GABA-B – G-Protein linked receptor
- Exclusively in the Retina
- GABA-C – ionotropic
The activation og GABA-A and GABA-C receptors allows the entry of Cl- into the neurons to mediate fast IPSP.
GABA-B is an example of GPCR(G-Protein Coupled Receptor) whose role is to alter the influx of Ca2+ and K+. Ca2+ influx is delayed or stopped, while a K+ channel is opened to allow flow down the gradient.
Drugs containing GABA receptor-binding substances(e.g. diazepam, or barbiturates) have an antianxiety activity, and work well as muscle relaxants, anticonvulsants and sedatives.
- Has both excitatory and inhibitory effects in the CNS
- When it binds to NMDA receptors it makes them more sensitive to Glu
- Also responsible for direct inhibition, primarily in the brainstem and spinal cord. It behaves like GABA (Increasing Cl- conductance).
Receptors for glycine:
- A receptor for Gly, a pentamer, that is also a Cl- ion channel.
Three kinds of neurons are responsible for direct inhibition in the spinal cord:
- Neurons that secrete GABA
- Neurons that secrete Glycine
- and Neurons that secrete both.
- Synthesised in the nerve terminal from choline(originating in the extracellular space) and acetyl-CoA (enzyme: Choline Acetyltransferase or ChAT)
Choline is taken up by the nerve terminal by a Na+ dependent Choline transporter.
- Neurons containing ACh vesicles at their terminals are termed Cholinergic neurons.
- All the neurons that exit the CNS (cranial nerves, motor neurons, & preganglionic neurons) are all cholinergic.
- Acetylcholine is released from the synapic vesicles when an impulse triggers the influx of Ca2+ into the nerve terminal.
- ACh is rapidly removed when repolarisation occurs. Enzyme: Acetyl Cholinesterase – Catalyses ACh hydrolysis.
Receptors for ACh:
- Muscarinic (Muscarine is a toxin in the toadstool that has stimulatori reactions over smooth muscle just like ACh, therefore the name).
- Nicotinic (Nicotine has stimulatory reactions over the sympathetic ganglia and skeletal muscle just like ACh, therefore the name).
- Nicotinic Cholinergic at Neuromuscular Junctions – N-m.
- Nicotinic Cholinergic in Autonomic Ganglia – N-n.
- Muscarinic Receptors:
- Are of five types (M1 to M5)
- Metabotropic receptors, coupled via G-proteins to adenylyl cyclase, K+ channels, and/or phospholipase C.
- M1; M4; M5 are found in the CNS
- M2 in the heart
- M3 on glands and smooth muscle.
- M1 also modulate neurotransmission in autonomic ganglia.
- Nicotinic Receptors:
- Are ligand-gated ion channels (ionotropic)
- Made of five subunits that form a central channel. They differ depending on the location of the receptor (ganglion or muscle).
- Permits the passage of Na+ and other cations.
- Many nicotinic cholinergic receptors are in the brain located presynaptically on Glu-secreting axon terminals where they facilitate the release of this transmitter. This is because they have a high permeability for Ca2+.
*Both Muscarinic and Nicotinic Receptors are found in the brain.
Biosynthesis and Release:
- Formed by hydroxylation and decarboxylations of the A.A. Tyrosine(Tyr)
- Some tyrosine is fromed from Phenylalanine(Phe) but most of it is from the diet.
- Tyrosine is transported into Catecholamine-secreting neurons by a Na+ dependent carrier.
- The rate-limiting step in the synthesis of catecholamines is the conversion of Tyr to DOPA, in the Neurons. This reaction is subject to feedback inhibition by dopamine and norepinephrine.
- DOPA Decarboxylase converts DOPA to Dopamine in the cytoplasm.
- Once synthesized, dopamine is transported into vesicles by VMAT, where it is converted to norepinephrine by dopamine B(beta)-hydroxylase.
Norepinephrine is the only small-molec. transmitter that is synthesized in synaptic vesicles.
- Some neurons in the CNS and Adrenal Medullary Cells also contain the cytoplasmic enzyme phenylethanolamine-N-methyltransferase. This catalyses the conversion of norepinephrine to epinephrine.
- Reuptake via a NET is a deactivation mechanism for norepinephrine, etc.
- Epinephrine and Norepinephrine are metabolized by:
- Monoamine Oxidase (MAO) – Oxidation on outer mitochondrial membrane. It is widely distributed in the body, but particularly occurs at nerve endings.
- Catechol-O-methyltransferase (COMT) – Methylation. It is widely distributed, but it is particularly found in the liver, kidneys, glial cells, but none in presynaptic noradrenergic neurons.
- Inactive derivatives are as such:
- 3,4-dihydroxymadelate + glycol (action of MAO)
- These substances can be monitored in the urine to measure the rate of secretion of those hormones.
Norepinephrine(Neuromodulator) and Epinephrine:
- I suppose they are called as such because they originate from around the kidney, i.e. adrenal medulla(greek “epi-nephros” = eng. “around-kidney.”)
- Norepinephrine – present at most symp. postggl. (sympathetic postganglionic) endings (the varicosities). Stored is synaptic knobs.
- Epinephrine is a methyl derivative of norepinephrine.
It is not present in symp. postggl.
- Both monoamines are also found in the brain(Noradrenergic/Adrenergic neurons).
- Soma of such neurons are located in locus coeruleus (lat. =English “blue spot”), and pontine nuclei.
Receptors of Norepinephrine and Epinephrine = Metabotropic:
- (α)Alpha-Adrenoreceptors, which have again subtypes (e.g. α-Adrenoreceptor Type 1A, or α-1A)
Are both acted upon by Norepinephrine and Epinephrine.
Again, Latin “adrenal” = Greek “epinephros” = around kidney in English, so everything is interconnected.
- Norepinephrine has a larger affinity for A-Adrenoreceptors. (A=α,)
- Epinephrine has a larger affinity for B-Adrenoreceptors
Most α1-adrenoreceptors are coupled via G proteins to phospholipase C, leading to the formation of IP3, and DAG (Diacylglycerol). This mobilises intracell. Ca2+ stores and activates protein kinase C.
- Synthesised from L-DOPA
- Located in multiple systems:
- Nigrostriatal system – Projects from Substantia nigra in Midbrain to the Striatum in the basal ganglia. It is involved in motor control.
- Mesocortical system – Arises in the ventral tegmentum, and projects to the ncl, accumbens and limbic subcortical areas. It is involved in reward behaviour and addictions, and in phychiatric disorders.
- Read about schizophrenia
- Are all metabotropic GPCR
- Can be categorised into:
- D1-like receptors: D1, and D5 – Increase cAMP levels
- D2-like receptors: D2, D3, and D4 – Lower cAMP levels
- Active reuptake occurs via Na+ and Cl- dependent dopamine transporter.
- Metabolised by MAO and COMT.
- Present in highest concentration in:
- Blood platelets,
- G.I.T. (enterochromaffin cells & myenteric plexus of Auerbach), and
- Brainstem (raphe nuclei projecting to hypothalamus, limbic system, neocortex, cerebellum and spinal cord).
- Syntesised from Tryptophan (Trp). The rate-limiting step is the conversion of Trp to 5-hydroxytryptophan.
- Taken up into the presynaptic neuron by serotonin transporter (SERT). Transported back into vesicles by VMAT. On the other hand it can be inactivated by MAO.
Receptors for Serotonin:
- There are 7 classes of 5-HT receptors (from 5-HT1 to 5-HT7)
- All receptors, except 5-HT3, are GPCR. They affect adenylyl cyclase or phospholipase C.
- Some are presynaptic, while others are postsynaptic.
- 5-HT2a = mediate platelet aggregation
- 5-HT2c = connected with obesity, and fatal seizures
- 5-HT3 = in G.I.T. and area postrema, related to vomiting
- 5-HT4 = in G.I.T., facilitate secretion and peristalsis
- 5-HT6 and 5-HT7 = in the brain. Have high affinity for antidepressants.
CLINICAL: Depression and LSD
The cause of depression is unknown, however there is strong evidence correlating depression with monoamine neurotransmitters. (norepinephrine, serotonin and dopamine)
Drugs such as LSD (lysergic acid diethylamide), or Psilocin (mushrooms) act by binding to Serotonergic Receptors.
- Derivative of Histidine (formed by decarboxylation).
- Histaminergic neurons are in tuberomammilary nucleus of post. hypothalamus.
Axons project to:
- Cortex, and
- Spinal cord.
- Histamine is also secreted by:
- Cells in the gastric mucosa
- Heparin-containing cells (Mast cells).
- The function of the diffuse histaminergic system is linked with arousal, sexual behaviour, blood pressure, drinking, pain tresholds, and regulation of secretion of several adenohypophyseal hormones.
Receptors for Histamine:
- There are four receptors:
- H1 – activate phospholipase C
- H2 – increase intracellular cAMP
- H3 – mediate inhibition of the realease of histamine and other transmitters via a G protein.
- H4 – plays a role in regulating cells of the immune system.
- Mediates rapid synaptic responses in the ANS
- Mediates fast response in the habenula.
(intersting article about the role of habenula in the control of dopamine release and addiction)
Receptors for ATP:
- P2x – ligand-gated
- P2y – GPCR
- P2u – GPCR
LARGE-MOLECULE TRANSMITTERS: NEUROPEPTIDES
- Polypeptide containing 11 AA
- Other members of the family include:
- neurokinin A
- neurokinin B
- The Intestine
- Peripheral Nerves
- Spinal cord: Primary afferent neurons
- Nigrostriatal system
Receptors for substance P:
- Neurokinin Receptors – All are Metabotropic receptors:
- NK1 – Substance P
- NK2 – neurokinin A
- NK3 – neurokinin B
- Spinal cord – Mediator at the first synapse in the pathway for pain transmission in the dorsal horn
- Nigrostriatal system – Concentration of substance P is proportional to that of dopamine
- Hypothalamus – Plays a role in neuroendocrine regulation.
- Intestine – Involved in Peristalsis
- Defined as substances(enkephalins) that bind to opioid receptors. Among enkephalins we count:
- pro-enkephalin(adrenal medulla)
- proopiomelanocortin(pro-opio-melano-cortin) (adenohypophysis)
- β-endorphin (also part of proopiomelanocortin)
- More than 20 have been identified.
Enkephalins are found in:
- Nerve endings in the G.I.T., and
Receptors for Opioids:
- μ (mu)
- κ (kappa)
- δ (delta)
All receptors are GPCR (Metabotropic), and inhibit adenylyl cyclase.
|Neurotransmitter with sensory input, locomotor activity,
and cognitive function.
Growth Hormone Inhibiting Hormone
Inhibits Insulin secretion and other pancreatic hormones
Inhibitory G.I.T. regulator
Inhibits adenylyl cyclase
|Neuropeptide Y||Brain and ANS||Mobilises Ca2+ and Inhibits adenylyl cyclase
Reduces release of norepinephrine
OTHER CHEMICAL TRANSMITTERS
Nitric Oxide (NO)
- Released by Endothelium
- Also produced in the brain
- Synthesised from Arginine, triggered by NMDA receptors
- Produced on demand, not stored.
- It is a gas, and crosses cell membranes with ease.
- It functions as a vasodilator, and it may also be involved with memory.
- Can be endogenous or exogenous
- Endogenous cannabinoids (anadaminde, etc.) are not stored either. They are produced on demand.
- They act on CB receptors, which has a high affinity for THC (tetrahydrocannabinol) the psychoactive ingredient in marijuana.
- The CB receptors trigger a G-protein mediated decrease in intracellular cAMP and is common in central pain pathways, as well as hippocampus, cortex and cerebellum.
- CB receptor agonists (substances that bind to them) have an anti-nociceptive effect, and induce euphoria.
A mediator(neurotransmitter) has multiple receptors.
Receptors can be found both on the pre, and the postsynaptic membranes.
Receptors can be either Ligand-Gated or G-Protein coupled. They are concentrated in clusters at areas of interest (e.g. where a mediator is secreted).
Receptors can become desensitized if they are exposed to their ligands too long.
1. Homologous desensitization = one receptor to one ligand is desensitized
2. Heterologous desensitization = multiple receptors are desensitized.
IPSP = Inhibitory Postsynaptic Potential
EPSP = Excitatory Postsynaptic Potential
(See Synaptic and Junctional Transmission for more).
Cathecolamines and monoamines are formed by hydroxylations and decarboxylations of Tyrosine.
Norepinephrine is the only small-molec. transmitter that is synthesized in synaptic vesicles.
MAO = Monoamine oxidase.
COMT = catechol-O-methyltransferase
Inactive derivatives of norepinephrine and epinephrine, produce by MAO and COMT, can be monitored in the urine to follow the production of those hormones.
Dopamine makes up two systems: Nigrostriatal system, and the mesocortical system.
The nigrostriatal system = movement, while mesocortical system = behavior, reward.
Serotonin is found in the cells of G.I.T., Brainstem, and Blood platelets. It is connected with Vomiting, Secretion in the G.I.T. and peristalsis, and depression.
Histamine is a derivative of Histidine. It is a neurotransmitter with a few receptors (H1 to H4) and it is involved in many functions among which immune response mediation.