Serotonin Receptors

“Serotonin (or 5-hydroxytryptamine) is one of the ancient signaling molecules, being produced and released by bacteria, in which it regulates swimming behavior and growth (1215).”

“Downloaded from spectively, perhaps neutralizing one another's effect (Murakami and Murakami 2007).”

“48 involved in conformational rearrangements of TM5 [24, 129].”

“The 5-hydroxytryptamine 1A (5-HT 1A ) serotonin receptor has been an attractive target for treating mood and anxiety disorders such as schizophrenia (Nichols and Nichols, 2008; Lacivita et al., 2012).”

“Detailed reviews regarding the different receptors involved and their action can be found elsewhere (e.g., Beaulieu and Gainetdinov, 2011; Hein, 2006; Nichols and Nichols, 2008; Thiele, 2013).”

“The 5-HT2ARs are widely expressed in the neocortex and hippocampus of rats (Xu and Pandey, 2000; Hannon and Hoyer, 2008), rabbits (Aloyo and Harvey, 2000), primates (Jakab and Goldman-Rakic, 1998; Lopez-Gimenez et al., 1998), and humans (Hoyer et al., 1986; Lopez-Gimenez et al., 1998).”

“…pathways through Gαi, Gαq/11, and Gαs, allowing this receptor family to modulate several biochemical signaling pathways, and leading to several physiological consequences, a discussion which is beyond the scope of this review, (but see Nichols and Nichols (2008) for a more comprehensive review).”

“the anxiolytic effects of 5-HT6Rs agonist and antagonist, it has been postulated that their role depends on the brain region (Żmudzka et al. 2018).”

“Both serotonergic type 1A and type 1B (5-HT1A and 5-HT1B) receptors are coupled to a Gi/o protein (Nichols and Nichols, 2008).”

“Since the discovery of the affinity of many atypical antipsychotics for the 5-HT6 receptor, this receptor has been investigated for putative cognitive enhancing effects (Roth et al., 2004; Mitchell & Neumaier, 2005).”

“In mammals, 14 (Htrs) have been described (Nichols and Nichols, 2008).”

“5-HT6 and 5-HT7 are grouped because they share a common G-protein, Gs [13].”

“Recent studies have demonstrated significant roles of D1 and D2 receptors in modulating synaptic plasticity and mediating cognitive dysfunction via cAMP/PKA signaling cascades, DARPP-32, and CREB modulation (Chang and Berg, 2001; Hu et al., 2002).”

“The serotonin receptors are divided into 7 families based on evolutionary lineage, sequence homology and intracellular effectors, designated 5-HT1R to 5-HT7R (Nichols and Nichols, 2008).”

“The serotonin receptor family is the largest family of GPCR neurotransmitter receptors (Nichols & Nichols, 2008) and is comprised of seven different receptor families (5-HT1-7).”

“Seven distinct families of serotonin receptors (numbered 5-HT1 to 5-HT7) have been identified so far, and subpopulations have been described for several of these [87].”

“For example, 5HT acts via seven different receptor subclasses, six of which are neuromodulatory and one ionotropic (Nichols and Nichols, 2008).”

“These receptors (all subtypes being GPCRs except for 5‐HT3) play a central role in neurobiology, affecting a multitude of functions in behavior, cognition and endocrine regulation, making their modulation an important objective in drug discovery.(132) More specifically, an attempt at designing a selective 5‐HT1B antag…”

“The best characterized 5-HT2A receptor-coupled signaling pathway is Gq/11-mediated activation of PLC, leading to the formation of inositol phosphates and diacylglycerol, followed by Ca release from the endoplasmic reticulum (Hannon and Hoyer 2008; Nichols and Nichols 2008; Raymond et al. 2001; Barnes and Sharp 1999).”

“These behaviors are mediated through interactions at seven different receptor families (5-HT1–7) comprised of 14 distinct subtypes (Nichols and Nichols, 2008).”

“These receptors mediate emotions and moods such as anxiety and aggression, cognition, sex, learning memory, appetite along with other biological, neurological and neuropsychiatric processes [8,10].”

“, lower blockade of and faster dissociation from the dopamine D2 receptor (Kapur and Seeman 2001) or the additional blockade of 5-HT2A receptors (Meltzer et al. 2003), may help to preserve some degree of dopaminergic neurotransmission in the ventral striatum, which then no longer differs significantly from healthy con…”

“Further, there is a high density of 5HT2A receptors in the brain, not only in cortex [1] but also in many distinct brain nuclei that can mediate peripheral processes like sympathetic activity [37].”

“Despite these pitfalls, it is well acknowledged that the serotonergic system and associated molecules expressed in immune cells can influence mood disorders, such as major depression [32] and schizophrenia [33, 34].”

“Serotonin binds to different receptor families (Nichols and Nichols, 2008), and here we will focus on the 5-HT1A receptor, which has previously been shown to interact with endogenous and exogenous cannabinoid ligands.”

“There are also dual receptors for dopamine (Civelli et al., 1991), adenosine (Ciruela et al., 2010), prostaglandins (Matsuoka & Narumiya, 2007) and serotonin (Nichols & Nichols, 2008).”

“The interaction with Gαi leads to inhibition of adenylyl cyclases, decreasing production of cAMP [5].”

“3 Serotonin receptor ligands Classification, structure, functions and ligands of serotonin receptors have been described in an excellent review [48].”

“The 5-HTR4, 5-HTR6, and 5-HTR7 family mainly act through the Gs family G proteins to stimulate adenylyl cyclase [146].”

“The complexity of the 5-HT system is further increased by alternative splicing and mRNA editing of several 5-HT receptors, their potential to form homo- or heterodimers, and crosstalk both within the 5-HT receptor family and with other receptor families [1, 2].”

“5-HT2 is coupled to Gq/11 that activates phospholipase C-β, which facilitates the release of diacyl glycerol and formation of inositol 1,4,5- trisphosphate (IP3) (169, 170).”

“■ REFERENCES (1) Hofmann, A. (1980) LSD: My Problem Child, McGraw-Hill, New York. (2) Shulgin, A. S. A. (1995) PIHKAL: Phenethylamines I have known and loved: a chemical love story, Transform Press, Berkeley. (3) Griffiths, R. R., Richards, W. A., McCann, U., and Jesse, R. (2006) Psilocybin can occasion mystical-type…”

“…• FEBRUARY 2011 • www.jn.org We did not expect a prominent role of the 5-HT2B receptor, which is a relatively obscure receptor, first described in the stomach fundus and not widely expressed in the brain (Barnes and Sharp 1999; Hoyer et al. 2002; Nichols and Nichols 2008; Wainscott et al. 1993).”

“5-HT1A Receptor Localization 5-HT1AR was the first 5-HTR subtype to be cloned and is characterized by its high affinity for 5-HT (Nichols and Nichols, 2008).”

“Of the 7 distinct families of mammalian 5-HT receptors, the 5-HT2 family of 5-HT receptors has, in humans, been most closely linked to neuropsychiatric disorders such as schizophrenia (Lieberman et al., 1998; Vollenweider et al., 1998; Meltzer et al., 2003).”

“To date, at least 14 5-HT receptors belonging to 7 families have been reported (Nichols and Nichols, 2008) and the 5- HT2A receptor (5HT2AR) may be one of the targets by which 5-HT modulates fear memory.”

“In both flies and mammals the effects of serotonin are primarily mediated through interactions with a number of G-protein coupled receptor proteins to initiate various effector pathways (Nichols and Nichols, 2008).”

“Neuronal excitability is modified by 5- HT via seven main types of receptors, 5-HT1−7, which are all G-protein coupled receptors (GPCRs) except for the ligandactivated 5-HT3 receptor (Boess and Martin, 1994; Hoyer et al., 2002; Nichols and Nichols, 2008).”

“[115,116]”

“With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G-protein-coupled receptor superfamily [3].”

“These 5-HT cells send ascending 5-HT fibers to many parts of the forebrain, and decreases in their rate of firing attenuate 5-HT release in their projection areas throughout the brain (Nichols and Nichols, 2008).”

“In addition, serotonergic and dopaminergic mechanisms also play an important role in opioidinduced respiratory depression as activation of 5-HT4(a), 5-HT7 and D1 receptors avert and reverse fentanyl-induced respiratory depression (Lalley, 2005; Manzke et al., 2003; Richter et al., 2003).”

“There are 7 classes of serotonin (5-HT) receptors (5-HT1 through 5-HT7) that are divided into 14 subfamilies (Nichols and Nichols, 2008).”

“as coronary artery, gastrointestinal tract, kidney, and spleen [3].”

“Introduction The brain serotonin and dopamine systems are each strongly associated with mood regulation, cognition, memory, learning, motivation and pleasure (Adayev et al., 2005; Arias-Carrion and Poppel, 2007; Bromberg-Martin et al., 2010; Nichols and Nichols, 2008).”

“There are seven distinct families of 5-HT receptors (5-HT1-7) and several subtypes (Nichols and Nichols 2008).”

“Of these, 5-HT1A and 5-HT1B are known to inhibit adenylate cyclase and 5-HT7 stimulates it, whereas 5-HT2 activation has not yet been investigated in Drosophila (reviewed in [25, 28]).”

“The 5-HT2-receptor family also includes the 5HT4, 5-HT6, and 5-HT7 receptors (Nichols and Nichols, 2008; Parsey, 2010).”

“Sequence motifs essential for ligand binding, receptor activation, and G-protein coupling typical for the 5-HT1 receptor subclass are well conserved in Am5-HT1A [17, 41].”

“INTRODUCTION The monoamine serotonin (5-HT) is widely distributed in the central nervous system (CNS), where it functions as neurotransmitter and neuro-hormone to control mood, circadian rhythm, nociception, hormone secretion, feeding and sexual behavior (Hannon and Hoyer, 2008; Nichols and Nichols, 2008).”

“Presently, vertebrate 5-HT receptors are divided into seven main 5-HT receptor families (termed 5-HT1-7) based on their gene organization, sequence similarities, pharmacological properties and downstream signaling pathways ([14,64,65,72-74]).”

“Studies indicate that serotonin receptor regulation and signal transduction pathways are diverse and complex.(89) For example, multiple scaffolding proteins and kinases regulate 5-HT 2A receptor function, and both agonists and some antagonists induce receptor down-regulation.”

“The GPCRs are divided into three major groupings according to whether they signal by coupling to Gαq/11 (5-HT2A, 5-HT2B and 5-HT2c), Gαi/o (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F and 5-HT5A/B) or Gαs (5-HT4, 5-HT6 and 5-HT7) G proteins [6].”

“Metabotropic serotonin receptors are coupled to different G-proteins including Gi (5-HT1 and 5-HT5), Gq (5-HT2) and Gs (5-HT4, 5-HT6 and 5-HT7) [252].”

“The 5-HT receptors are the target of a variety of pharmaceutical drugs, including many antidepressants, antipsychotics, etc [39], so cinitapride may be effective in the treatment of mental disorders.”

“…this explanation unlikely since 18F-altanserin has been shown to have a 5-HT2A vs. 5-HT2C receptor selectivity ratio of 20 (Tan et al., 1999), and in cerebral cortex the expression of 5-HT2A is higher than 5-HT2C receptors (Appel et al., 1990; Pompeiano et al., 1994; Nichols and Nichols, 2008).”

“At least 14 serotonin receptor subtypes have been identified (Nichols and Nichols, 2008; Palacios, 2016).”

“Given that 5-HT receptors are widely expressed in the human brain (Beliveau et al., 2017), they have important functions in the regulation of mood states, instinctual drives, sleep, and dreaming (Nichols and Nichols, 2008; Pace-Schott, 2008).”

“In mammals, it exerts its action through 14 different receptor subtypes that comprise seven distinct families (5-HT1–7) (34).”

“There is some evidence that ‘normal’ levels are associated with calmness and emotional stability (Young, 2007), while low levels are implicated in negative affect, and mental health issues such as depression and anxiety (Żmudzka et al., 2018).”

“expressed at high levels in the hepato-gastrointestinal (GI) tract, including the liver [8].”

“…intracellular transduction mechanisms: 5HT 1 (mostly G α i ; subtypes 5HT 1A, 5HT 1B, 5HT 1D, 5HT 1E, 5HT 1F ), 5HT 2 (G α q ; subtypes 5HT 2A , 5HT 2B , 5HT 2C ), 5HT 3 (ionotropic), 5HT 4 (G α s and G α i ), 5HT 5 (G α i ; subtypes 5HT 5A , 5HT 5B ), 5HT 6 (G α s ), and 5HT 7 (G α s ) [186, 187].”

“A total of seven families of 5-HT receptors (5-HT1 through 5-HT7) and at least 14 different subtypes have been identified so far (Nichols and Nichols, 2008; Muit et al., 2022).”

“It is of note that many of these receptors have been validated to be the targets of a variety of pharmaceutical drugs, including many well-known antidepressants (Nichols and Nichols, 2008).”

“Serotonergic receptors (Gq-coupled 5-HT2) are responsible for mobilizing Ca2+ levels in oocytes which in turn, leads to the hydrolysis of inositol phosphate and an increase in cytosolic Ca2+ levels (81).”

“The effects of serotonin are primarily mediated through interactions with several G-protein coupled receptors to initiate multiple signal transduction pathways (Raymond et al., 2001, Nichols and Nichols, 2008).”