3.3.2 Receptor structure and function
Knowledge of Receptor Structure and Function in Relation to the Neurotransmitters
| Neurotransmitter: | Pathway: | Rate limiting step: | Breakdown enzymes: | Breakdown product: | Reuptake channel: | Receptors: |
| Acetylcholine | Acetyl coenzyme A (acetyl CoA, which is synthesized from glucose) and choline | Choline concentration | Choline acetyltransferase | Acetylcholinesterase | Acetylcholine is degraded by the enzyme acetylcholinesterase, and the products may be recycled through high-affinity transporters on the nerve terminal. | Muscarinic receptors (G-protein coupled): M1, M2, M3, M4 and M5. Nicotinic receptors (ion channels). |
| Dopamine | Tyrosine → L-DOPA → Dopamine | Tyrosine hydroxylase | Monoamine oxidase (MAO): MAO-A = noradrenaline + serotonin. MAO-B = dopamine. | Homovanillic acid | Dopamine transporter Note: cocaine inhibits this transporter. | D1, D2, D3, D4 and D5 (G-protein coupled). |
| GABA | GABA is synthesized in the cytoplasm of the presynaptic neuron from the precursor glutamate by the enzyme glutamate decarboxylase | Glutamic acid decarboxylase | GABA transaminase | GABA can be degraded extracellularly or taken back up into the glia or the presynaptic cell. GABA taken up from the synapse into the neurons is reused for synaptic loading. GABA taken up by astrocytes is degraded into C02 and glutamine. Glutamine is transported into the neurons for glutamate and GABA synthesis. | GABA at the synapse is terminated by reuptake into both presynaptic nerve terminals and surrounding glial cells. | GABAA: inhibitory and opens chloride channel. GABAB: G-protein coupled. |
| Glutamate | Multiple sources | Accumulation of precursors | Glutamate dehydrogenase | Glutamine or alpha-ketoglutarate. | Glial cell uptake with conversion to glutamine. | Metabotropic and ionotropic (NMDA, kainate binding or AMPA type). |
| Noradrenaline | Tyrosine → L-DOPA → Dopamine → Noradrenaline → Adrenaline | Tyrosine hydroxylase | Monoamine oxidase (MAO) + Catechol-O-methyltransferase (COMT) | Vanillyl mandelic acid | Noradrenaline reuptake channels | Alpha and beta. |
| Serotonin | Tryptophan → 5-hydroxy tryptophan → Serotonin | Tryptophan availability | MAO-A | 5-hydroxy indole acetic acid (5-HIAA) | Serotonin reuptake channels | 14 subtypes of serotonin receptors. |
(Brady, 2012)
Acetylcholine receptors:
Acetylcholine (Ach) receptors are made of four polypeptide chains: it contains two α subunits and a β, γ and δ. In the CNS and PNS for fast neuron transmission acetylcholine receptors and neuronal nicotinic acetylcholine receptors play a meditating role. These receptors also work in physiological and pathological functions. Ach receptors modulate an array of functions such as arousal, learning, memory, rapid eye movement sleep, pain perception, thirst and parasympathetic mediation. There is reduced cholinergic function in Alzheimer’s dementia.
Dopamine receptors:
Dopamine receptors are very important for our daily life activities. Dopamine plays an essential role in the brain function related to emotions, movement and system of reward (addictions) and motivation. In the central nervous system, dopamine receptors are expressed particularly in the subventricular area and hippocampal dentate gyrus. Dopamine consists of five receptors, every receptor has a different role to perform (D1, D2, D3, D4, D5). In Parkinson’s disease levels of dopamine are low, whereas in psychosis especially in the mesolimbic area dopamine is high.
| Dopamine receptor: | Function: |
| D1 | Memory and attention regulations, impulse control, locomotion, and renal function regulation. |
| D2 | Attention, locomotion, learning, sleep patterns, and memory. |
| D3 | Attention and sleep regulations, and cognition impulse control. |
| D4 | Responsible for neuronal signalling in the mesolimbic system of the brain, a part of the brain that regulates emotion and complex behaviour. |
| D5 | Cognition, renin secretion, and decision making. |
GABA receptors:
GABA functions as a primary inhibitor neurotransmitter. Its main function is to lessen neuronal excitability. In the central nervous system, it slows down GABA by blocking particular signals. In your central nervous system, it provides a calming effect. It’s also important for handling the nerve cell hyperactivity that is linked to stress, anxiety and fear. GABA receptors are the point of action for benzodiazepines, barbiturates and alcohol, this has applications in seizure cessation.
Glutamate receptors:
Glutamate receptors, which are found on both neuronal and non-neuronal cells, mediate rapid excitatory synaptic transmission in the central nervous system. These receptors are responsible for a wide range of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors also have a crucial metabolic role since they act as an intermediary in the oxidation pathway.
Noradrenaline receptors:
The noradrenergic system serves several functions in the central and peripheral neural systems. It plays an important role in the body’s “fight or flight” response. Noradrenaline and adrenaline are released during stressful or anxious states and bind to adrenergic receptors throughout the body, causing effects such as dilating pupils and bronchioles, increasing heart rate and constricting blood vessels, increasing renin secretion from the kidneys, and inhibiting peristalsis.
Noradrenaline has also been demonstrated to stimulate glycogenolysis and gluconeogenesis (despite decreasing glucose clearance) and to induce ketogenesis and lipolysis (Hussain, 2022).
Serotonin receptors:
Serotonin plays a vital role in body functions such as mood, digestion, nausea, blood clotting, sexual function, wound healing, sleep and pain perception. The serotonin hypothesis of depression postulated in the 1960s was the idea a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. In recent years there is little evidence to support this (Moncrieff, 2022).
There are 14 known subtypes of serotonin receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, 5-HT5B, 5-HT6, and 5-HT7). Some functions are shown below:
| Serotonin receptor: | Function: |
| 5-HT3 | All except 5-HT3 are G-protein coupled receptors; 5HT3 is predominant in the gut; associated with motility. |
| 5-HT1A | G-protein coupled postsynaptically; antidepressant response; sexual behaviour. |
| 5-HT1B | G-protein coupled presynaptically. |
| 5-HT1D | G-protein coupled are both presynaptic and postsynaptic. |
| 5-HT2 | Phospholipase C coupled; postsynaptic; antagonism leads to antipsychotic response (atypicals) and sedation. LSD causes 5-HT2 stimulation. Down-regulation was noted after antidepressant treatment or electroconvulsive therapy. |
| 5-HT6 | May be involved in antidepressant action. |
| 5-HT7 | Regulation of the circadian rhythm. |
Excitatory amino acids:
Excitatory amino acids (EAA) are used by the vast majority of synapses in the central nervous system. An amino acid neurotransmitter is an amino acid which is able to transmit a nerve message across a synapse. Neurotransmitters are packaged into vesicles that cluster beneath the axon terminal membrane on the presynaptic side of a synapse.
Examples of EAA:
- Aspartic acid
- Cysteine
- Glutamic acid/glutamate
- Homocysteine
- Aspartate
(Levitan, 2002).
The functional physiological range of glutamate and glutamate receptors is extremely limited, and even little deviations produce a slew of neurological and psychological problems via excitotoxicity. Excitotoxicity of glutamate appears to play a role in schizophrenia and Alzheimer’s disease (Birbaumer, 1999).
Pre-synaptic and post-synaptic receptors:
Presynaptic receptors are regions where transmitters, locally produced mediators, or hormones restrict or facilitate transmitter release from axon terminals. Presynaptic terminals are like small buds and contain organelles, seen with help of a light microscope. Synaptic vesicles are filled with neurotransmitters. At the end of the axon, a presynaptic terminal converts the electric current of the action potential into chemical signals via neurotransmitter release (Schlicker, 2017).
Synaptic vesicles are small sacs inside where neurotransmitters are stored and neurotransmitters released in the synaptic cleft, it occurs when a vesicle fuses with the cell membrane via exocytosis. Exocytosis occurs in less than a millisecond releasing the neurotransmitter.
Neurotransmitters interact with receptor proteins on the membrane of the postsynaptic cell after being released into the synaptic cleft, causing ionic channels on the membrane to open or close. Depolarization happens when these channels open, resulting in the activation of another action potential (Purves, 2017).
There are two types of post-synaptic receptors that recognize neurotransmitters ionotropic receptors (ligan-gate ion channels) and metabotropic receptors (G-protein coupled receptors) (Hollingsworth, 1991).
References:
(1) Brady, S.T., Siegel, G.J., R Wayne Albers and Price, D.L. (2012). Basic neurochemistry : principles of molecular, cellular, and medical neurobiology. Waltham, Massachusetts ; Oxford: Academic Press / Elsevier.
(2) Birbaumer, N. and Flor, H. (1999). Applied Psychophysiology and Biofeedback, 24(1), pp.35–37. doi:10.1023/a:1022838829332.
(3) Hollingsworth, P. J. and Smith, C. B. (1991) “Factors influencing the function of presynaptic α2-adrenoceptors in rat brain,” in Presynaptic Receptors and Neuronal Transporters. Elsevier, pp. 39–42.
(4) Hussain, L.S., Reddy, V. and Maani, C.V. (2022). Physiology, Noradrenergic Synapse. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK540977/#:~:text=During%20states%20of%20stress%20or [Accessed 16 Mar. 2022].
(5) Levitan, I.B. and Kaczmarek, L.K., 2002. The neuron: cell and molecular biology. Oxford University Press, USA.
(6) Moncrieff, J., Cooper, R.E., Stockmann, T., Amendola, S., Hengartner, M.P. and Horowitz, M.A. (2022). The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry, pp.1–14. doi:10.1038/s41380-022-01661-0.
(7) Purves, D., Augustine, G.J., Fitzpatrick, D., Katz, L.C., Anthony-Samuel LaMantia, McNamara, J.O. and S Mark Williams (2017). Two Families of Postsynaptic Receptors. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK10855/.
(8) Schlicker, E. and Feuerstein, T. (2017). Human presynaptic receptors. Pharmacology & Therapeutics, [online] 172, pp.1–21. doi:10.1016/j.pharmthera.2016.11.005.