Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABA_A receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.

生理上，心房首先收缩，然后心室收缩，这是血液正常循环的前提。上述房室序贯收缩现象是由于心房和心室之间的房室结（AVN）电兴奋的特征性缓慢传导所致。然而，尚不清楚是什么控制着 AVN 内的电激励传导。在这里，我们发现 AVN 起搏细胞（AVNPC）拥有完整的内在 GABA 能系统，该系统在从心房到心室的电传导中发挥着关键作用。首先，随着在 AVNPC 表面膜下发现丰富的含有 GABA 的囊泡，在 AVNPC 中鉴定出了 GABA 能系统的关键元件，包括 GABA 代谢酶、GABA 受体和 GABA 转运蛋白。其次，GABA同时在AVNPC中引发GABA门控电流，这显着削弱了AVNPC的兴奋性。第三，GABA能系统的关键分子元件显着调节AVN中电激发的电导率。第四，AVNPC 中的 GABA _A 受体缺乏会加速房室传导，从而损害 AVN 对快速心室频率反应的保护潜力，增加对致命性室性心律失常的易感性，并降低心脏收缩功能。最后，针对GABA能系统的干预措施有效预防了房室传导阻滞的发生和发展。总之，AVNPC 中的内源性 GABA 能系统决定了 AVN 内电兴奋的缓慢传导，从而保证顺序房室收缩。 内源性 GABA 能系统有望成为心律失常的新型干预靶点。