Discovery of the 5-HTR1E Serotonin Receptor: Function & Importance in Brain Health

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The neurotransmitter serotonin plays many important roles in our brains and bodies by binding to various serotonin receptor proteins.

One of these receptors, called 5-HTR1E, has remained mysterious even after its discovery over 30 years ago.

Facts about 5-HTR1E receptor:

  • It is one of the 13 known serotonin receptor proteins that serotonin can bind to and activate.
  • 5-HTR1E is part of the 5-HT1 group of serotonin receptors, which all have similar structures and functions.
  • It is found in the brains of humans and some animals like guinea pigs, but is not present in rat or mouse brains.
  • 5-HTR1E has been detected in areas of the brain involved in functions like smell, movement, cognition and mood regulation.
  • When activated by serotonin, 5-HTR1E can trigger signaling pathways involved in cell survival, proliferation, and protection against stress.
  • Abnormal 5-HTR1E levels have been associated with neurological diseases and cancers, suggesting it may play roles in these conditions.

After three decades of work, scientists are still just beginning to uncover the importance of the enigmatic 5-HTR1E receptor in the brain.

Source: Cell Commun Signal. 2023

The Discovery of the 5-HTR1E Receptor

The story of 5-HTR1E began in 1988, when scientists studying serotonin receptors found evidence of an unknown receptor site that serotonin could bind to in the human brain.

They designated this mystery site 5-HTR1E, naming it after the serotonin 1 (5-HT1) family of receptors it resembled.

Initial studies suggested 5-HTR1E was abundant in areas of the cortex and hippocampus – regions involved in functions like sensory perception, cognition, learning and memory.

However, its distribution and role in the brain remained unclear.

Over the next few years, researchers cloned the gene for 5-HTR1E and identified the receptor in brain tissues from humans, guinea pigs and chickens.

But intriguingly, they were unable to find 5-HTR1E in rodent brains.

The Structure and Location of 5-HTR1E Receptors

Like other 5-HT1 receptors, 5-HTR1E is a G protein-coupled receptor with 7 domains that span the cell membrane.

When the neurotransmitter serotonin binds to 5-HTR1E, it triggers a cascade of signaling within the cell.

5-HTR1E is expressed in specific areas of the brain:

  • The olfactory bulb, involved in the sense of smell
  • The hippocampus, important for memory and learning
  • The cortex, which controls abilities like sensory perception and movement
  • The amygdala, hypothalamus and midbrain regions that regulate mood and behavior

Its localization to these key brain areas suggests 5-HTR1E may play a role in important neurological functions.

But surprisingly, after 30 years its functions are still not fully understood.

Possible Roles of 5-HTR1E in the Brain

Although the precise functions of 5-HTR1E remain mysterious, recent research is starting to uncover some of activities of this long-overlooked serotonin receptor:

Smell

The highest levels of 5-HTR1E are found in the olfactory bulb – the area responsible for the sense of smell. This indicates 5-HTR1E may be involved in odor perception and processing.

Learning and Memory

5-HTR1E is abundant in the hippocampus, which controls learning and memory. It may help regulate signaling pathways involved in the formation of new memories.

Movement

Significant 5-HTR1E expression in the cortex suggests it could contribute to control of sensory perception and motor activities like movement and coordination.

Mood and Behavior

5-HTR1E is present in midbrain regions like the amygdala and hypothalamus, which govern mood, anxiety, fear and other behaviors. It may help modulate these responses.

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Neuroprotection

Recent research found that activating 5-HTR1E triggers pathways involved in neuron survival.

This could indicate a role in protecting brain cells from injury and disease.

5-HTR1E Signaling Pathways

When serotonin binds to 5-HTR1E, the receptor relays signals inside the cell through various pathways:

  • It inhibits the enzyme adenylate cyclase, which reduces cyclic AMP levels. This alters many cell processes.
  • It activates a signaling cascade involving the proteins ERK and AKT, influencing cell growth and survival.
  • It stimulates Ras and Rap, small proteins involved in cell proliferation and differentiation.
  • It recruits the protein β-arrestin, activating pathways that promote neuron survival.
  • It inhibits the protein SRC, thereby reducing cell proliferation pathways linked to cancer.

Through these complex cascades, 5-HTR1E activation can modulate diverse cell functions like growth, metabolism, and stress responses.

The Mysterious Pharmacology of 5-HTR1E

Compared to other serotonin receptors, researchers have struggled to identify drugs and compounds that potently and selectively bind 5-HTR1E.

This is partly because 5-HTR1E shares high similarity with its sibling receptor 5-HTR1F.

Many drugs thought to target 5-HTR1E also interact with 5-HTR1F.

So far, only a handful of drugs have been found that somewhat preferentially bind 5-HTR1E over other serotonin receptor subtypes:

  • BRL54443
  • Ergonovine
  • Methysergide
  • Sumatriptan

Development of new selective drugs for 5-HTR1E would aid future efforts to decipher its roles.

5-HTR1E in Health and Disease

Although still poorly understood, some early links have been found between 5-HTR1E and conditions like cancer and neurodegeneration:

Neurological Disorders

  • Lower 5-HTR1E levels were seen in brain tissues from Alzheimer’s patients.
  • Variations in the 5-HTR1E gene may be associated with increased risk of Parkinson’s disease.

This hints 5-HTR1E disruption could contribute to some neurodegenerative diseases.

Cancer

  • 5-HTR1E expression was reduced in human ovarian tumors and associated with poorer prognosis.
  • Knocking out 5-HTR1E in ovarian cancer cells increased cell proliferation pathways.

Conversely, 5-HTR1E may act as a tumor suppressor in certain cancers.

Depression, OCD

  • Changes in 5-HTR1E have been found in patients with depression and suicide victims.
  • Certain 5-HTR1E gene variants occur more frequently in people with obsessive-compulsive disorder.

5-HTR1E could play a role in mood disorders, but this requires more study.

The Future of 5-HTR1E Research

While many gaping holes remain in our understanding of 5-HTR1E, the receptor is finally starting to reveal some of its secrets after 30 years of mystery.

Ongoing and future research priorities for this long-overlooked serotonin receptor include:

  • Developing new drugs to precisely target 5-HTR1E over related receptors
  • Studying 5-HTR1E’s functions in animal models like guinea pigs
  • Exploring its roles in the hippocampus, cortex and other brain regions
  • Understanding its links to diseases like Alzheimer’s, Parkinson’s and cancer
  • Investigating if it could be a new drug target for treating certain conditions
  • Figuring out exactly how 5-HTR1E activation regulates complex signaling pathways
  • Using advanced techniques like cryo-EM to solve its 3D structure at atomic resolution

While many questions remain unanswered, scientists are optimistic that a clearer picture of the mysterious 5-HTR1E receptor will gradually emerge through ongoing research – perhaps leading to exciting new insights into brain function and guiding development of novel therapeutics.

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