Bringing Structure to Biology
Depression and neurotransmitters
Depression, a common mental disorder
While a depressed mood is a normal temporary reaction to life events, a symptom of some physical diseases, or sometimes a side effect of some drugs and medical treatments, depression is a common mental disorder characterized by a persistent sadness and lack of interest in previously enjoyable activities. According to the World Health Organization, depression is a leading cause of disability around the world, and its effects can be long-lasting, dramatically affecting a person’s ability to live a rewarding life.
All the electrochemical activity of our brain and body propagates along nerve cells called axons. Axons make contact with other cells – usually other axons, or muscle or gland cells – at junctions called synapses, where the membrane of an axon closely adjoins the membrane of the other cell. Chemical synapses use molecules called neurotransmitters, which will interact with receptors located on the target cell, allowing the transmission of the signal from a nerve cell to another across the synaptic gap. Neurotransmitters are therefore chemical messengers responsible for transmitting the information throughout the brain and the rest of the body.
Although the physiopathology of depression is not yet fully understood, pharmacological treatments exist. One of the first theories about the cause of depression, is that a deficit of certain neurotransmitters would lead to depressive symptoms. Therefore, many commercialized antidepressants act on the chemical balance of neurotransmitters in the brain. Those antidepressant drugs drastically increase synaptic levels of certain neurotransmitters, among which serotonin and dopamine. Sleep deprivation and light therapy are also known to target the same brain neurotransmitter system as antidepressant drugs, and are both used clinically to treat depression.
Neurotransmitter sodium symporters
Nerve cells convert electrical impulses into bursts of chemicals, called neurotransmitters, which travel across the synapses to receptors and transporters on adjacent cells, triggering electrical impulses to travel down the latter cells. These specific transport proteins clear the synapse after a nerve signal, transporting neurotransmitters back into the axon and making it ready for another signal.
Neurotransmitter sodium symporters (NSS) are a family of proteins capable of catalysing the passage of a variety of neurotransmitters across the cell membrane by a solute:Na+ symport mechanism, with the transport of the sodium ions and neurotransmitters in the same direction. This co-transport is powered by the gradient of sodium ions which generates a difference of electric potential between the inner and extracellular space, thus making the process energetically favourable and allowing NSS proteins to transport neurotransmitter molecules into the nerve cells against their concentration gradient. This transport is not dependent on other sources of energy (for example, ATP).
LeuTAa, a bacterial homologue of mammalian neurotransmitter sodium symporters
The protein which inspired the image for October in our 2020 calendar is the leucine:2 Na+ symporter from the eubacterium Aquifex aeolicus, LeuTAa (2.A.22.4.2, Uniprot ID O67854), a prokaryotic homologue of mammalian sodium neurotransmitter symporters. LeuTAa was one of the first NSS family members to be crystallized, and was therefore used to gain structural knowledge on its mammalian homologues.
NSS are integral membrane proteins sharing a common structure of 12 hydrophobic alpha helices, that form a transport channel through the membrane, as can be seen from the LeuTAa structure PDB ID 2Q72. Both the sodium ions and the leucine amino acid bind to the centre of the protein, at the high affinity binding site.
Besides the sodium ions and the leucine amino acid, the molecule bound in the structure 2Q72 is Depramine, a tricyclic antidepressant (TCA), specifically a dibenzazepine, possessing three rings fused together with a side chain attached in its chemical structure.
Depramine binds in a large extracellular-facing cavity at the outer entrance of LeuTAa. This low-affinity allosteric site is about 11Å above the leucine and two sodium ions, apparently slowing the rate at which leucine dissociates from LeuTAa, and stabilizing the extracellular gate in a closed conformation. This shows that TCAs inhibit NSS proteins by slowing their substrate release in a non-competitive manner.
Many TCAs were developed in the 1960s, and even if Depramine was never commercialized, one closely related molecule, Desipramine, which differs only by one methyl group, is currently used in the treatment of depression.
Two structures of LeuTAa with Desipramine are available in the PDB archive: 2QJU and 2QB4. Desipramine acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as a weak serotonin reuptake inhibitor. Desipramine is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in the event of an overdose.
About the artwork
This piece is inspired by mental illness and how diseases such as depression can occupy the mind. The dark swirling background surrounding the silhouette of a person encapsulates feelings related to mental illness. The brain is depicted in bright colours, highlighting the activity of the mind in these conditions. Overlaid onto the brain is the structure of a neurotransmitter transporter, a protein that is important for conveying signals in the brain. Bleach was used purposefully and artistically to create the colour change around the swirling patterns, mirroring the way that depression removes the colour from someone’s life. Combination of print, photoshop and ink drawing, by Imogen Phillips, a student from the Stephen Perse Foundation.
Structures mentioned in this article
LeuTAa with Depramine: 2Q72