Positive inotrophic effect by stimulation of serotonin receptors in failing hearts

Andrea Hembre Ulsund has looked into the interaction between G protein-coupled receptors and serotonin receptors, as well as intracellular cAMP signaling elicited by 5-HT4 serotonin receptors in normal and failing hearts.


MAIN RESULTS:

  1. 5-HT4 serotonin receptor stimulation induces positive inotrophy in failing hearts through cAMP signalling more efficiently than β adrenergic receptors.
  2. The 5-HT7 serotonin receptor are associated with Gs protein coupling in the absence of ligand.

THESIS DEFENCE:

Thesis: G protein coupling and signaling of Gs-coupled serotonin receptors
Candidate: Andrea Hembre Ulsund
Time: September 10, 2019 at 13:15
Place: University of Oslo, Domus Odontologica: Store auditorium
Link to university website


SUMMARY:

(3) Stimulation of the 5-HT4 serotonin receptor in failing hearts induces a positive inotrophic effect. This happens through cAMP messaging. 5-HT4 appears to be more efficiently coupled to contractility than β adrenergic receptors, as cAMP increase is lower but contractility the same. Further research showed that 5-HT4-dependent cAMP increase was compartmented close to the contractile apparatus of the cell, in near proximity of troponin I. Phosphodiesterase 4 appears downregulated in heart failure, increasing the contribution of phospodiesterase 3 on cAMP activation.

(1/2) The 5-HT7 serotonin receptor and the G-proteins coupled to it are associated even in the absence of ligand, as opposed to the 5-HT4 and β adrenergic receptors. Agonist activation of 5-HT7 leads to conformational change of the Gα subunit and a slow dissociation of the Gγ subunit from both the receptor and Gα. Ulsund’s research finds that the same domains responsible for this preassociation are involved in low potency activation of adenylyl cyclase.


REFERENCES:

(1) Andressen, K. W., Ulsund, A. H., Krobert, K. A., Lohse, M. J., Bünemann, M., & Levy, F. O. (2017). Related GPCRs couple differently to Gs: preassociation between G protein and 5-HT7 serotonin receptor reveals movement of Gαs upon receptor activationThe FASEB Journal32(2), 1059-1069.

(2) Ulsund, A. H., Dahl, M., Frimurer, T. M., Manfra, O., Schwartz, T. W., Levy, F. O., & Andressen, K. W. (2018). Preassociation between the 5-HT7 serotonin receptor and G protein Gs: molecular determinants and association with low potency activation of adenylyl cyclaseThe FASEB Journal33(3), 3870-3886.