Figure 12.

Scheme. 5-HT signaling via 5-HT₄-receptors and LPS signaling in TG cardiac myocytes. Stimulation of cardiac 5-HT₄-receptors in the sarcolemma of transgenic mice leads to stimulation of adenylate cyclase (AC) via stimulatory G-proteins (Gs). AC increases cAMP levels in the cytosol, where it can either directly activate HCN channels and thereby increase the beating rate in sinoatrial cells or can activate the cAMP-dependent protein kinase (PKA). PKA can increase Ca²⁺-cycling by phosphorylation of phospholamban (PLB) on serine 16 or of the L-type Ca²⁺ channel (LTCC) or of the ryanodine receptor (RyR). Ca²⁺ is released via the ryanodine receptor, increasing Ca²⁺ levels near the myofibrils, which increases the force of contraction at the beginning of systole. Relaxation is initiated by sarcoplasmic Ca²⁺ ATPase (SERCA), which pumps Ca²⁺ into the sarcoplasmic reticulum at the beginning of diastole. Phosphorylation of these proteins is reduced in part by the catalytic subunit of protein phosphatase 2A (PP2A) and, conversely, the action of PP2A is reduced at least in part by activation of the 5-HT₄ receptor. Lipopolysaccharide (LPS) can bind to a complex of TLR4 and CD14. This leads via intracellular signaling pathways to increased gene transcription in the nucleus. Here, an interaction between 5-HT₄ receptor signaling and LPS signaling appears questionable.