HTR4 Membrane Protein Introduction

Introduction of HTR4

5-hydroxytryptamine receptor 4 (HTR4), alternatively called serotonin receptor 4, is a G protein-coupled receptor (GPCR) that is identified as one of the several different receptors for 5-hydroxytryptamine (serotonin). HTR4 is encoded by HTR4 gene in human and is expressed in the alimentary tract, urinary bladder, heart, and adrenal gland as well as the central nervous system (CNS). And particularly in the CNS, HTR4 is found in the putamen, caudate nucleus, nucleus accumbens, globus pallidus, and substantia nigra, and to a lesser extent in the neocortex, raphe, pontine nuclei, and some areas of the thalamus.

Function of HTR4 Membrane Protein

HTR4 receptors mediate both excitatory and inhibitory neurotransmission and modulate the release of many neurotransmitters including glutamate, GABA, dopamine, epinephrine/norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, and cortisol. HTR4 functions in both the peripheral and central nervous system such as sleep/wake cycle, thermoregulation, food intake, nociception, locomotion, sexual behavior, gastrointestinal motility, blood coagulation, and cardiovascular homeostasis, by modulating the release of various neurotransmitters. The activity of HTR4 is mediated by G proteins that stimulate adenylate cyclase and promote cAMP formation. HTR4 has been implicated in inflammatory hyperalgesia and is supposed to enhance inflammatory pain. The protein p11 was identified as an HTR4-interacting protein. p11 protein may increase HTR4 surface expression in COS-7 cells and facilitates HTR4 signaling. Studies have shown that an HTR4 agonist partially has antidepressant-like effects in rodent models of depression.

Fig.1 Schematic representation of serotonin (5-HT) in the terminal and synapse. (Vinkers, 2010)

Application of HTR4 Membrane Protein in Literature

1. Deen M., et al. High brain serotonin levels in migraine between attacks: A 5-HT4 receptor binding PET study. Neuroimage Clin. 2018, 18:97-102. PubMed ID: 29387527
   
   

   The results of this article showed that lower 5-HT4 receptor binding in migraine patients was suggestive of higher brain 5-HT levels and indicated that high brain 5-HT levels may represent a trait of the migraine brain or it could be a consequence of migraine attacks.

2. Nedi T., et al. Effect of the 5-HT4 receptor agonist tegaserod on the expression of GRK2 and GRK6 in the rat gastrointestinal tract. BMC Res Notes. 2018, 11(1):362. PubMed ID: 29884229
   
   

   This study was designed to assess the effect of 5-HT4 receptor activation on the expression of GRK2 and GRK6 in the rat esophagus and distal colon by acute administration of tegaserod and indicated that the basal level of GRK2 and GRK6 expression was sufficient to regulate the desensitization of 5-HT4 receptors in acute drug treatment.

3. Mine Y., et al. DSP-6952, a novel 5-HT4 receptor partial agonist, inhibits visceral hypersensitivity and ameliorates gastrointestinal dysfunction in experimental animals. Eur J Pharmacol. 2018, 826:123-132. PubMed ID: 29428470
   
   

   This article concluded that DSP-6952, a novel and orally available 5-HT4 receptor agonist, induced colonic GMCs, enhanced colonic transit, increased defecation without inducing diarrhea, improved drug-induced delay in whole-gut transit, and inhibited visceral hypersensitivity in experimental animals.

4. Castello J., et al. CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior. Mol Psychiatr. 2018, 23(4):872-882. PubMed ID: 29158580
   
   

   The findings of this study identified the mPFC (mouse prefrontal cortex) as the region that mediated the effect of enhanced 5-HT4 receptor activity and CK2 as a modulator of 5-HT4 receptor levels in this brain region that regulated mood-related phenotypes.

5. Jean A., et al. Adaptive control of dorsal raphe by 5-HT4 in the prefrontal cortex prevents persistent hypophagia following stress. Behav Brain Res. 2017, 21(4):901-909. PubMed ID: 29069597
   
   

   Authors of this study suggested that when mPFC-5-HT4Rs were overexpressed and DR-5-HT1ARs were blocked in the DR, hypophagia following stress persisted, suggesting an antidepressant action of early anorexia.

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Reference

1. Vinkers C H, et al. (2010). Stress-induced hyperthermia: the serotonin system and anxiety. Open Pharmacology Journal. 4:15-29.

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