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Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands.

Chilmonczyk Z, Bojarski AJ, Pilc A, Sylte I - Int J Mol Sci (2015)

Bottom Line: The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu.Moreover, receptor trafficking appears different at pre- and postsynaptic sites.Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

View Article: PubMed Central - PubMed

Affiliation: National Medicines Institute, Chełmska 30/34, 00-725 Warszawa, Poland. z.chilmonczyk@nil.gov.pl.

ABSTRACT
Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

No MeSH data available.


Related in: MedlinePlus

Signal transduction pathways of the 5-HT1A receptor [22,23,24].
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ijms-16-18474-f002: Signal transduction pathways of the 5-HT1A receptor [22,23,24].

Mentions: The primary coupling linkage of the 5-HT1A receptor (and of all 5-HT1 receptors) is to the inhibition of adenylate cyclase (AC) and decrease protein kinase A (PKA) activity. However, the 5-HT1A receptor couples to the broadest panel of second messengers of any of the 5-HT receptors [21]. This receptor has been reported to activate or inhibit various enzymes, channels, and kinases, and to stimulate or inhibit production of diverse soluble second messengers. The receptor has been found to inhibit and activate AC and phospholipase C (PLC), to stimulate nitric oxide synthase (NOS) and a nicotinamide adenine dinucleotide phosphate (NADP) oxidase-like enzyme, to activate K+ channels and high conductance anion channels, to inhibit Ca2+ conductance and inhibit or stimulate Ca2+ mobilization, and regulate a number of channels and transporters (Figure 2) [22,23,24]. The 5-HT1A receptor can activate protein kinase C (PKC), Src kinase, and mitogen-activated protein kinases (MAPKs), activate or inhibit phosphatidyl inositol hydrolysis, and stimulate production of reactive oxygen species (both H2O2 and superoxide) and arachidonic acid [1].


Functional Selectivity and Antidepressant Activity of Serotonin 1A Receptor Ligands.

Chilmonczyk Z, Bojarski AJ, Pilc A, Sylte I - Int J Mol Sci (2015)

Signal transduction pathways of the 5-HT1A receptor [22,23,24].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581256&req=5

ijms-16-18474-f002: Signal transduction pathways of the 5-HT1A receptor [22,23,24].
Mentions: The primary coupling linkage of the 5-HT1A receptor (and of all 5-HT1 receptors) is to the inhibition of adenylate cyclase (AC) and decrease protein kinase A (PKA) activity. However, the 5-HT1A receptor couples to the broadest panel of second messengers of any of the 5-HT receptors [21]. This receptor has been reported to activate or inhibit various enzymes, channels, and kinases, and to stimulate or inhibit production of diverse soluble second messengers. The receptor has been found to inhibit and activate AC and phospholipase C (PLC), to stimulate nitric oxide synthase (NOS) and a nicotinamide adenine dinucleotide phosphate (NADP) oxidase-like enzyme, to activate K+ channels and high conductance anion channels, to inhibit Ca2+ conductance and inhibit or stimulate Ca2+ mobilization, and regulate a number of channels and transporters (Figure 2) [22,23,24]. The 5-HT1A receptor can activate protein kinase C (PKC), Src kinase, and mitogen-activated protein kinases (MAPKs), activate or inhibit phosphatidyl inositol hydrolysis, and stimulate production of reactive oxygen species (both H2O2 and superoxide) and arachidonic acid [1].

Bottom Line: The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu.Moreover, receptor trafficking appears different at pre- and postsynaptic sites.Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

View Article: PubMed Central - PubMed

Affiliation: National Medicines Institute, Chełmska 30/34, 00-725 Warszawa, Poland. z.chilmonczyk@nil.gov.pl.

ABSTRACT
Serotonin (5-HT) is a monoamine neurotransmitter that plays an important role in physiological functions. 5-HT has been implicated in sleep, feeding, sexual behavior, temperature regulation, pain, and cognition as well as in pathological states including disorders connected to mood, anxiety, psychosis and pain. 5-HT1A receptors have for a long time been considered as an interesting target for the action of antidepressant drugs. It was postulated that postsynaptic 5-HT1A agonists could form a new class of antidepressant drugs, and mixed 5-HT1A receptor ligands/serotonin transporter (SERT) inhibitors seem to possess an interesting pharmacological profile. It should, however, be noted that 5-HT1A receptors can activate several different biochemical pathways and signal through both G protein-dependent and G protein-independent pathways. The variables that affect the multiplicity of 5-HT1A receptor signaling pathways would thus result from the summation of effects specific to the host cell milieu. Moreover, receptor trafficking appears different at pre- and postsynaptic sites. It should also be noted that the 5-HT1A receptor cooperates with other signal transduction systems (like the 5-HT1B or 5-HT2A/2B/2C receptors, the GABAergic and the glutaminergic systems), which also contribute to its antidepressant and/or anxiolytic activity. Thus identifying brain specific molecular targets for 5-HT1A receptor ligands may result in a better targeting, raising a hope for more effective medicines for various pathologies.

No MeSH data available.


Related in: MedlinePlus