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Query: UNIPROT:P08908 (
5-HT1A
)
5,574
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Serotonin
5-HT1A
-type and beta-adrenergic receptors have similar molecular characteristics, which explains why certain substances like propranolol have affinities for both receptor types. Activation of
5-HT1A
receptors leads to a decrease in intracellular cAMP levels whereas the opposite occurs for beta-adrenergic receptors. Both
5-HT1A
and beta-adrenergic receptors exist in the rabbit ciliary processes. Topical application of the
5-HT1A
agonist, 8-hydroxydipropylaminotetralin (8-OH-DPAT) reduces
intraocular pressure
(
IOP
). beta-Antagonists are also known to reduce
IOP
. It is postulated that substances which have an affinity for
5-HT1A
and/or beta-adrenergic receptors and lead to a reduction in intracellular cAMP levels in the ciliary processes diminish
IOP
.
...
PMID:Do beta-adrenoceptors and serotonin 5-HT1A receptors have similar functions in the control of intraocular pressure in the rabbit? 887 15
Various classes of compounds exist to lower
intraocular pressure
(
IOP
) in the treatment of glaucoma. None of them is ideal since some patients respond better than others and the side effects vary between individuals. New classes of compounds need to be introduced to allow the clinician greater scope for effective treatment of all patients. It is now generally agreed that the cause of ganglion cell dysfunction in glaucoma is likely to be multifactorial and that concentrating solely on reducing
IOP
is inadequate. Irrespective of the reason for the dysfunction, the future goal must be to attenuate cell death. This may be achieved with drugs that interact with components of the retina, and is termed 'neuroprotection'. Thus, drugs that can both reduce
IOP
and act as neuroprotectants would be ideal for the treatment of glaucoma. In this article we summarise studies on animals which show serotonergic
5-HT1A
agonists to both reduce
IOP
when topically applied to the rabbit eye and blunt the damaging effect to the rat retina and ganglion cells induced by glutamate toxicity or ischaemia. Reduction of
IOP
occurs via stimulation of
5-HT1A
receptors associated with the ciliary processes. Neuroprotection of retinal neurones appears to involve the interaction of
5-HT1A
agonists with membrane sodium channels and/or
5-HT1A
or even possibly 5-HT7 receptors. Various
5-HT1A
agonists are used in patients to treat depression, so classes of these drugs have a proven safety profile for use in patients. The animal studies summarised in this article suggest that
5-HT1A
agonists need to be considered as a new class of drugs for the treatment of glaucoma.
...
PMID:5-Hydroxytryptamine1A agonists: potential use in glaucoma. Evidence from animal studies. 1102 74
Published investigations of serotonin-1A (5-hydroxytryptamine1A;
5-HT1A
) receptor agonists and serotonin-2A (5-hydroxytryptamine2A; 5-HT2A) receptor antagonists in nonprimate species provide conflicting results with regard to their
intraocular pressure
-lowering efficacy. Thus, their therapeutic utility in the treatment of human glaucoma has been confusing. We evaluated the effect of selected
5-HT1A
agonists and 5-HT2A receptor antagonists on
intraocular pressure
in a nonhuman primate model, the conscious cynomolgus monkey with laser-induced ocular hypertension. Neither selective
5-HT1A
agonists [e.g., R-8-hydroxy-2-(di-n-propylamino)tetralin and flesinoxan] nor selective 5-HT2 receptor antagonists [e.g., R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M-100907) and 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxamide (SB-242084)] lowered
intraocular pressure
in the primate model following topical ocular administration. However, compounds that function as agonists at both the
5-HT1A
and 5-HT2 receptors were found to effectively lower
intraocular pressure
in the model: 5-hydroxy-alpha-methyltryptamine, 5-methoxy-alpha-methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-methoxy-N,N-dimethyltryptamine. Furthermore, the selective 5-HT2 receptor agonist R-(-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane lowered
intraocular pressure
in the primate model, demonstrating a pharmacological response associated with activation of the 5-HT2 receptor. These observations suggest that compounds that function as efficient agonists at 5-HT2 receptors should be considered as potential agents for the control of
intraocular pressure
in the treatment of ocular hypertension and glaucoma in humans.
...
PMID:Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys. 1267 87
Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists are neuroprotective in CNS injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), a serotonin receptor (
5-HT1A
) agonist, in an adult male Wistar rat model of chronic glaucoma model remain unknown. We found that ocular hypertension decreased
5-HT1A
receptor expression in rat retinas because the number of retinal ganglion cells (RGCs) was significantly reduced in rats with induced ocular hypertension relative to that in control retinas and 8-OH-DPAT enhanced the RGC viability. The protective effects of 8-OH-DPAT were blocked by intravitreal administration of the selective
5-HT1A
antagonist WAY-100635 or the selective GABA
A
receptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic IPSCs (sIPSCs and mIPSCs, respectively) of RGCs in rat retinal slices were recorded. 8-OH-DPAT significantly increased the frequency and amplitude of GABAergic sIPSCs and mIPSCs in ON- and OFF-type RGCs. Among the signaling cascades mediated by the
5-HT1A
receptor, the role of cAMP-protein kinase A (PKA) signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by PKA inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of phosphorylated PKA (p-PKA)/PKA was significantly increased in glaucomatous retinas and 8-OH-DPAT significantly decreased p-PKA/PKA expression, which led to the inhibition of PKA phosphorylation upon relieving neurotransmitter GABA release. These results showed that the activation of
5-HT1A
receptors in retinas facilitated presynaptic GABA release functions by suppressing cAMP-PKA signaling and decreasing PKA phosphorylation, which could lead to the de-excitation of RGC circuits and suppress excitotoxic processes in glaucoma.
SIGNIFICANCE STATEMENT
We found that serotonin (5-HT) receptors in the retina (
5-HT1A
receptors) were downregulated after
intraocular pressure
elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic IPSCs (mIPSCs) in ON- and OFF-type retinal ganglion cells (RGCs) and RGCs in normal and glaucomatous retinal slices. Therefore, phosphorylated protein kinase A (PKA) inhibition upon release of the neurotransmitter GABA was eliminated by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), which led to increased levels of GABAergic mIPSCs in ON- and OFF-type RGCs, thus enhancing RGC viability and function. These protective effects were blocked by the GABA
A
receptor antagonist SR95531 or the
5-HT1A
antagonist WAY-100635. This study identified a novel mechanism by which activation of
5-HT1A
receptors protects damaged RGCs via the cAMP-PKA signaling pathway that modulates GABAergic presynaptic activity.
...
PMID:Activation of 5-HT1A Receptors Promotes Retinal Ganglion Cell Function by Inhibiting the cAMP-PKA Pathway to Modulate Presynaptic GABA Release in Chronic Glaucoma. 3054 12
