Functional interaction of H2-receptors and 5HT4-receptors in atrial tissues isolated from double transgenic mice and from human patients

Abstract

In the past, we generated transgenic mice that overexpress the human histamine 2 (H2)-receptor (H2-TG) or that overexpress the human serotonin 4 (5-HT4)-receptor (5-HT4-TG) in the heart. Here, we crossbred these lines of mice to generate double transgenic mice that overexpress both receptors (DT). This was done to study a conceivable interaction between these receptors in the mouse heart as a model for the human heart. When in left atria, initially, force of contraction was elevated maximally with 1 µM serotonin, and subsequently, histamine was cumulatively applied; a biphasic effect of histamine was noted: the force of contraction initially decreased, maximally at 10 nM histamine, and thereafter, the force of contraction increased again at 1 µM histamine. Notably, functional interaction between 5-HT and histamine was also identified in isolated electrically stimulated trabeculae carneae from human right atrium (obtained during cardiac surgery). These functional and biochemical data together are consistent with a joint overexpression of inotropically active H2-receptors and 5-HT4-receptors in the same mouse heart. We also describe an antagonistic interaction on the force of contraction of both receptors in the mouse atrium (DT) and in the human atrial muscle strips. We speculate that via this interaction, histamine might act as a “brake” on the cardiac actions of 5-HT via inhibitory GTP-binding proteins acting on the activity of adenylyl cyclase.

The Roles of Cardiovascular H2-Histamine Receptors Under Normal and Pathophysiological Conditions

“…Further evidence indicates that the order of drug application is important for H 2 -histamine receptors and other receptors that are coupled to the activity of adenylyl cyclase. For example, if the cardiac serotonin 4 (5-HT 4 ) receptor (i.e., the receptor mediating the positive inotropic effect of serotonin in the human heart) was first stimulated, then H 2 R activation decreased the force of contraction but not vice versa ( Neumann et al, 2019 ; Neumann et al, 2021d ). These data are in line with the assumption that H 2 -histamine receptors are coupled via inhibitory and stimulatory G-proteins with the activity of adenylyl cyclase in the heart.…”

“…When generated, cAMP then activates a cAMP-dependent protein kinase (PKA), which then phosphorylates typical targets in the heart ( Figure 1A ). Some of these targets are still hypothetical substrates, such as the ryanodine receptor, whereas others have been shown in transgenic mice (phospholamban, phosphatase inhibitor 1) ( Gergs et al, 2019 , 2020 , 2021b ; Neumann et al, 2021d ). Moreover, H 2 R stimulation can increase the phosphorylation state of the inhibitory subunit of troponin (TnI) and the myocardial C-protein.…”

“…Nevertheless, mice have advantages because they are somewhat easier to keep and breed. Moreover, they could be crossbred with KO mice or other transgenic mice to study in detail cardiac signal transduction in the heart ( Schwarzer et al, 2019 ; Gergs et al, 2020 ; Neumann et al, 2021d ). Other approaches have also been successfully used.…”

Cardiovascular effects of bufotenin on human 5-HT4 serotonin receptors in cardiac preparations of transgenic mice and in human atrial preparations

“…We have likewise utilized this model to study in some detail the effect of hypertrophy, sepsis, hypoxia, and ischemia on the cardiac function of 5-HT 4 receptors (Gergs et al 2021a ). Likewise, we have used this model to predict an interaction of 5-HT 4 and H 2 histamine that we then could confirm in human atrial preparations (Neumann et al 2021b ). We have shown early on that stimulation of 5-HT 4 receptors occurs on cardiomyocytes in transgenic mice and leads to increase in currents through L-type Ca 2+ channels and increased levels of free calcium ions in the cytosol in systole (Gergs et al 2010 ).…”

Serotonin Receptors in Myocardial Infarction: Friend or Foe?

“…183 The 5-HT4R has been shown to interact with the 5-HT2AR and the histamine receptor, both of which are also present in cardiac tissue. 184,185 More recently, we demonstrated the physical interaction between 5-HT2AR and receptor kinase B as well as 5-HT7R and CD44. 186,187 Therefore, pharmacological modulation of selective 5-HTRs might subsequently change signaling of their interaction partners.…”