Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The human 5-HT1A receptor was expressed in Sf9 insect cells to examine desensitization as manifested by agonist-induced uncoupling from G proteins and second messengers. New binding sites were detected after infection of cells with the 5-HT1A receptor-bearing baculovirus. 5-HT1A receptor agonists caused inhibition of cAMP accumulation that could be attenuated by specific receptor antagonists. Brief pretreatment with 5-HT resulted in (1) an uncoupling of receptor from G proteins as evidenced by a loss of high-affinity agonist binding sites and a diminished ability of the receptor to increase incorporation of AA-GTP into endogenous Go alpha-like G proteins, (2) a decreased ability of the receptor to inhibit cAMP accumulation, and (3) increased phosphorylation of the 5-HT1A receptor on serine and threonine residues. Phosphorylation occurred in the presence of a number of cyclic nucleotide dependent kinase inhibitors, and desensitization of the cAMP response occurred in the presence of H-7 and also in cells with prolonged exposure to PMA. Both phosphorylation and desensitization were markedly attenuated by 100 nM and 1 microM heparin and demonstrated similar time courses and concentration-response relationships. Those results demonstrate a close association between agonist-induced desensitization and phosphorylation of the 5-HT1A receptor in Sf9 cells through a pathway that mainly does not involve protein kinase A or C and might involve a G protein-linked receptor kinase.
 ...
PMID:Agonist-induced desensitization and phosphorylation of human 5-HT1A receptor expressed in Sf9 insect cells. 754 32

The serotonin 5-HT1B and 5-HT1A receptors bind certain beta-adrenergic antagonists, such as propranolol and pindolol, with high affinity. Other 5-HT1 receptors that display very low affinity for beta-adrenergic antagonists, have either a threonine (T) (5-HT1D alpha, 5-HT1D beta and 5-HT1E) or an alanine (A) (5-HT1F) residue in the homologous position in the seventh transmembrane domain. In the case of the human 5-HT1D beta receptor, replacement of this T with asparagine (N), dramatically increases its ability to bind beta-adrenergic antagonists. To assess whether other 5-HT1 receptors would behave similarly, we have used site-directed mutagenesis to replace the T or A in 5-HT1D alpha, 5-HT1E and 5-HT1F receptors with N. Both the wild-type and mutant genes were expressed transiently in COS-7 cells and radioligand binding studies were performed by using [3H]5-HT and [125I]iodocyanopindolol. Using [3H]5-HT, we found that the affinities of all the mutant receptors for propranolol and pindolol were significantly increased by 100-1000 fold, 5-HT1D alpha and 5-HT1F receptors showing the highest and the 5-HT1E receptor displaying the lowest affinity. On the other hand, the affinities for 5-HT were essentially unchanged as compared to the wild-type receptors. All mutant receptors bound [125I]iodocyanopindolol with high affinity, KD values ranging between 0.04 nM (mutant 5-HT1D alpha) and 0.57 nM (mutant 5-HT1E), whereas the wild-type receptors failed to show any specific binding with this radioligand in the same concentration range used for the mutant receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:A single point mutation increases the affinity of serotonin 5-HT1D alpha, 5-HT1D beta, 5-HT1E and 5-HT1F receptors for beta-adrenergic antagonists. 798 76

We have identified a conserved threonine residue in the second intracellular (i2) loop of the 5-HT1A receptor that when mutated to alanine prevents coupling to G beta gamma-mediated signaling, while preserving G alpha i-induced actions. In this review, we investigate the characteristics and potential role of the i2 domain in the coupling of the 5-HT1A receptor and other receptors to G proteins. The i2 domain, as well as portions of the i3 domain, is predicted to form an amphipathic alpha-helix with a positively charged face and a hydrophobic face. Mutagenesis experiments support a model in which the hydrophobic faces of these alpha-helical domains form an intracellular binding "pocket" for interaction with G proteins. Embedded in the hydrophobic face, Thr 149 is crucial for signaling through G beta gamma subunits, perhaps via interaction with its hydroxyl side-chain. Mutation of other residues of the i2 domain of Gi-coupled receptors is required to substantiate the importance of the alpha-helical i2 domain in receptor-G beta gamma signaling. If confirmed in other receptors, these results support a general model in which activated receptor and G beta gamma subunits remain associated to interact with effectors in a receptor-specific manner.
 ...
PMID:A putative alpha-helical G beta gamma-coupling domain in the second intracellular loop of the 5-HT1A receptor. 992 52

Mice lacking the serotonin receptor 1A [Htr1aknock-out (Htr1a(KO))] display increased innate and conditioned anxiety-related behavior. Expression of the receptor in the mouse forebrain during development is sufficient to restore normal anxiety-related behavior to knock-out mice, demonstrating a role for serotonin in the developmental programming of anxiety circuits. However, the precise developmental period as well as the signaling pathways and neural substrates involved in this phenomenon are unknown. Here, we show that pharmacological blockade of the receptor from postnatal day 13 (P13)-P34 is sufficient to reproduce the knock-out phenotype in adulthood, thus defining a role for serotonin in the maturation and refinement of anxiety circuits during a limited postnatal period. Furthermore, we identify increases in the phosphorylation of alpha-Ca(2+)/calmodulin-dependent protein kinase II (alphaCaMKII) at threonine 286 in the hippocampus of young Htr1a(KO) mice under anxiety-provoking conditions. Increases in alphaCaMKII phosphorylation were most pronounced in the CA1 region of the hippocampus and were localized to the extrasynaptic compartment, consistent with a tissue-specific effect of the receptor. No changes in alphaCaMKII phosphorylation were found in adult knock-out mice, suggesting a transient role of alphaCaMKII as a downstream target of the receptor. Finally, the anxiety phenotype was abolished when knock-out mice were crossed to mice in which alphaCaMKII phosphorylation was compromised by the heterozygous mutation of threonine 286 into alanine. These findings suggest that modulation of alphaCaMKII function by serotonin during a restricted postnatal period contributes to the developmental programming of anxiety-related behavior.
 ...
PMID:Alpha-Ca2+/calmodulin-dependent protein kinase II contributes to the developmental programming of anxiety in serotonin receptor 1A knock-out mice. 1855 Jul 67