Signal transduction

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Signal transduction is the mechanism by which a signal is transmitted through cell to induce the appropriate response. Most psychoactive drugs influence signal transduction of neurons by interacting with extracellular receptors - either activating them, blocking them or changing the way they are activated by endogenous ligands (known as allosteric modulation). Others, such as most stimulants or MAO inhibitors, affect the metabolism or transport of endogenous ligands. However, understanding the ways drugs act on specific intracellular signaling components is an interest of many researchers, as it can provide better insights to the nature of their effects and potential dangers .

General overview

A signal transduction pathway generally includes a lignad, a receptor, primary and secondary effectors and “secondary messengers”.

Ligand

A ligand is any chemical that binds to a receptor. Endogenous ligands are of various chemical nature, including proteins, amines, amino acids, or even gases. Ligands that mediate signal between neurons are called neurotransmitters. Some psychoactive drugs directly “imitate” neurotransmitters, but the ligand-receptor binding is complicated and usually cannot be predicted by simple similarity in 2D structure alone . Neurons usually create only one type of “true” neurotransmitter, but can additionally produce some neuromoduolators (sometimes less accurately also referred to as neurotransmitters ) like various peptides, cannabinoids, or nitric oxide. Receptors for corresponding neurotransmitters are also expressed differently in different neurons. This creates neurotransmitter pathways or systems, which are associated with specific functions in the brain. Examples of neurotransmitters:

• Glutamate
• GABA
• Acetylcholine
• Dopamine
• Serotonin
• Noradrenaline
• Endogenousopioids (mostly rather neuromodulatory function)

Examples of other relevant ligands:

• Neurotrophic factors - role in neurogenesis and mood, possibly responsible for the anitdepressant effects of ketamine
• Developmental pathways (Akt/mTOR, Notch, Hedgehog, Wnt…) - these are negatively affected in a developing fetus if the mother consumes certain drugs.

Receptor

A receptor is a specialized protein that detects the presence of a stimulus - such as mechanical force, light, or a ligand. Receptors can be present on the cell membrane, but also inside the cell. Drugs and most endogenous ligands usually target extracellular receptors, because they are not able to enter the inside of the cell. However, for example amphetamines activate the intracellular Trace amine associated receptor (TAAR) - which likely mediates at least some of their effects - as they can enter the cell by being transported with transporters for dopamine or noradrenaline.

Most common extracellular receptors are:

• Ligand gated ion channels - these are channels in the membrane that open when activated by ligands. When open, they let specific ions (Na+, Ca2+, K+, Cl-…) either in or out of the cell, which changes the membrane potential and allows for very fast signal transmission. Examples of ligand gated ion channels include NMDA receptors - targets of dissociatives, or GABA-A receptors - targets of many depressants.
• G-protein coupled receptors - most common receptors in animal cells, when activated they pass the signal to an associated trimeric G protein. This is a small protein that travels on the intracellular side of the membrane and activates or inhibits the production of secondary messengers. There different types of GPCRs, and can be both excitatory and inhibitory. Examples include serotonin receptors (except for 5HT3) - targets of most psychedelics or opioid receptors.
• Receptors with enzymatic activity - most commonly tyrosine kinases, when activated they start catalyzing a biochemical reaction. This reaction is usually phosphorylation which activates/deactivates other enzymes or signaling components. Examples are receptors for growth factors.

Secondary messengers

“Secondary messengers” is an arbitrary term for several small molecules that are able to transfer and amplify signal inside of the cell. These are:

• Calcium ions - an important signaling component in many processes in the brain. Too much calcium can induce cell death. This is why NMDAR antagonists, like ketamine or memantine have neuroprotective effects and can be used for the treatment of Alzheimer’s disease .
• Inositol triphosphate and diacylglycerol - these molecules is released after cleavage of membrane lipids catalyzed by phospholipase C. This process is most commonly activated by GPCRs with a G_{alpha q} subunit (for example 5HT2A). However, both DAG and IP3 in turn increases calcium concentration, so PLC signaling is linked with Ca signaling.
• Cyclic AMP - a molecule produced by the enzyme adenylate cyclase, activated by GPCRs with a G_{alpha s} subunit (for example D1) and inhibited by G_{alpha i} (for example GABA-B). The effects of cAMP are mostly mediated through protein kinase A.

Enzymatic effectors

Most complicated part of signal transduction are these large molecules. Most common enzymes involved in signaling are kinases - enzymes that catalyze the addition of phosphate to a molecule. In cells, phosphate serves as a switch that either activates or deactivates the molecule’s involvement in biochemical reactions. A large group of kinases, known as protein kinases, add phosphates to other proteins. This often results in complex cascades of phosphorylation, in which kinases phosphorylate other kinases, often several times before the signal is complete .

Response

A signal transduction pathway can induce a cellular response in various ways, usually multiple at once. The fastest response is the change in membrane potential by the transport of ions. After the potential is increased, more channels, voltage-gated ion channels, open and result in amplification of the signal. These electrical signals are how brain allows for constant communications between many neurons. Change in membrane potential doesn’t have to be a result of ligand-gated channel activaiton. Opioid receptors signaling, for example, includes the opening of potassium channels which is partially responsible for its analgesic effects .

Another possible response is the change in metabolic processes of the cell. Many signaling pathways affect the intake, decomposition or synthesis of nutrients.

The final effect of a signaling pathway is the change in gene expression. This is mediated by transcription factors that bind to the DNA in the nucleus. This can result in significant long-term effects on the whole organism. Change in gene expression is thought to play a role in the development of addiction or tolerance.