The gut microbiota metabolite phenylacetylglycine regulates cardiac Ca2+ signaling by interacting with adrenergic receptors

TL;DR

A gut microbiota metabolite called PAGly affects heart function by altering calcium signaling through adrenergic receptors.

Contribution

This study reveals that PAGly modulates cardiac calcium dynamics via adrenergic receptors, partially blunting the effects of adrenergic agonists.

Findings

PAGly increases cytosolic Ca2+ transients and SR Ca2+ load in mouse ventricular myocytes.

PAGly's effects on Ca2+ dynamics are mediated through adrenergic receptors and PKA.

PAGly reduces the stimulatory effect of adrenergic agonists on intracellular Ca2+.

Abstract

Phenylacetylglutamine (PAGln) and phenylacetylglycine (PAGly) are small molecules derived from the metabolism of phenylalanine by gut microbiota. Elevated levels of PAGln and PAGly in serum have been associated with increased risks for cardiovascular diseases. It has been suggested that PAGln and PAGly reduce cardiac contraction by blunting the adrenergic response during sympathetic stimulation. However, little is known whether the effect of PAGln and PAGly on the heart function is associated with an alteration of intracellular Ca2+ homeostasis. Here, we studied the effect of PAGly on Ca2+ regulation in mouse ventricular myocytes, as PAGly is the predominant phenylalanine metabolite in rodent’s serum. Analysis of cytosolic Ca2+ dynamics revealed that PAGly (100 μM) increases action potential-induced Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ load. These effects of PAGly were significantly smaller than those produced by the adrenergic receptor agonist isoproterenol (ISO; 0.1 μM). The adrenergic receptor blocker propranolol (10 μM) and the protein kinase A (PKA) inhibitor H89 (10 μM) prevented the PAGly effects on intracellular Ca2+ dynamics. Further analysis of Ca2+ regulation revealed that pretreatment of cardiomyocytes with PAGly reduced the stimulatory effect of ISO on intracellular Ca2+ dynamics. Concurrently, PAGly did not produce any stimulatory effects on intracellular Ca2+ in the presence of ISO. In conclusion, PAGly regulates intracellular Ca2+ dynamics in ventricular myocytes by activating the adrenergic receptor-mediated signaling, but less efficiently than selective adrenergic agonists. By interacting with adrenergic receptors, PAGly can partially blunt the stimulatory effect of adrenergic receptor agonists.

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