The completion of the human genome project in 2003 allowed for the identification of the many subreceptors, gene promoter variants, and single nucleotide polymorphisms that all contributed to individual variations to drugs. More recently, the field of epigenetics has exploded, which adds yet another complex layer to gene expression. Significantly, an individual’s experiences throughout life have been shown to affect and change these epigenetic factors.
To appreciate just how far we have come since the FDA approval of iproniazid in 1958, let us explore the peeling of just the serotonin onion (Table 4). Three scientists who were studying hypertension at the Cleveland Clinic in 1948 discovered a molecule released from platelets that resulted in vasoconstriction, synergistically working with the platelets to stop bleeding. They named this new vasoconstrictor serotonin. Subsequently, it was established that 90% of serotonin is in the gastrointestinal tract, and the remaining 10% is in the brain and in platelets.
The next challenge was to discover serotonin’s role in the 3 organ systems. A serotonin receptor was discovered, which created a logical sequence of information flow: serotonin is released from a presynaptic serotonin neuron and through entropy drifts across the synapse (Figure). As it drifts, some of the serotonin binds to and activates the serotonin post-synaptic receptor. Binding to this receptor activates a change across the post-synaptic neuron’s membrane. If the receptor is ionotropic (an ion channel that is opened or closed), the receptor affects the influx or outflux of a particular ion relevant to that receptor. If the receptor is metabotropic (a G-protein transmembrane-linked receptor), it results in many possible intracellular processes that can ultimately affect induction or suppression of gene expression, or activation or suppression of numerous intracellular processes.
The first serotonin receptor discovered was named the 5HT-1 receptor. Further research found a distinct second serotonin receptor, named 5HT-1B, while the first serotonin receptor was renamed 5HT-1A. In addition, a third serotonin receptor was identified: 5HT-1C. Careful analysis of these receptors’ amino acid sequences, and the discovery of additional serotonin receptors, indicated that there were different “families” of receptors that bound serotonin. Consequently, because of differences in their amino acid sequences, these serotonin receptors could be subdivided by similarities and differences.
The 5HT-1C receptor was structurally more similar to the 5HT-2A and 5HT-2B receptors than to the other 5HT-1 receptors, so it was renamed 5HT-2C. To this day, there is no 5HT-1C receptor, but we now have 5HT-1D, 5HT-1E, and 5HT-1F receptors.
In 1993 the seventh and final family of serotonin receptors was discovered, appropriately named the 5HT-7 receptor. With the completion of the human genome sequencing in 2003, it is well accepted that there are no additional families of serotonin receptors. Having so many variations for the activation of any given G-protein at the cell surface allows for infinite possibilities of post-synaptic neuronal response to a single neurotransmitter, such as serotonin.
However, it would be too easy if the story ended here. Each gene that codes for the mRNA of each receptor contains introns and exons, which allows each serotonin subreceptor to be spliced in alternative sequences, providing another layer of complexity.
A single gene for a single receptor can have a range of single nucleotide polymorphisms (SNPs) that preserve the functioning of the gene but result in a range of binding affinity variability or response variability for the same neurotransmitter—in this case, serotonin. The change in a single nucleotide of one gene can occur in many different locations, each of which can alter the gene’s function in different ways. The SNPs can occur on the promoter sequence preceding the gene, which can affect the number of gene products transcribed—affecting the final number of receptors in the neuron’s membrane.
Alternatively, SNPs can occur at some structural site in the gene, which can directly affect the 3-dimensional structure of the neurotransmitter-receptor interface, or have a distant allosteric effect on the receptor that also influences receptor function. In both cases, the SNP on the structural region of the receptor’s gene can result in 3 different outcomes: no change in receptor activity, a decrease in receptor activity, or an increase in receptor activity.
One of the many studies that resulted from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial supports this idea of heterogeneity. McMahon and colleagues1 report, “Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele.”