True hibernators are remarkable group of mammals whose hearts are resistant to such stressors as deep hypothermia, ischemia, arrhythmia. Capability of cardiac cells from hibernating species to effectively rule Ca²⁺ homeostasis during torpor is poorly studied. Better understanding of these mechanisms could allow to introduce new strategies for improvement the cardiac performance and may be useful for cardiovascular medicine. Here for the first time we have shown that the regulation of Ca²⁺ handling and thereby cardiomyocyte contractility by endogenous neurotransmitter agmatine occurs through the modulation of calcium-sensing receptor (CaSR). In isolated cardiocytes of hibernating ground squirrels generating stationary Ca²⁺ transients in the absence of actual myocellular excitation, low doses of this polyamine (up to 500 μM) induce the G_βγ-dependent activation of PI₃-kinase with subsequent stimulation of Akt-kinase and nitric oxide (NO) production by endothelial NO-synthase (eNOS). NO production abolishes Ca²⁺ oscillations in virtue of the enhancement of Ca²⁺ reuptake by sarco(endo)plasmic Ca²⁺ ATPase (SERCA). Simultaneously, the activation of phospholipase A₂ (PLA₂) and arachidonic-acid dependent Ca²⁺ entry occur providing replenishment of Ca²⁺ store. High concentrations of agmatine (> 2 mM) induce other CaSR-mediated pathways involving phospholipase C (PLC) pathway, the formation of inositoltriphosphate (IP₃) and diacylglicerol (DAG) followed by induction of their targets: IP₃ receptors and protein kinase C isoforms (PKC), respectively. Furthermore, it is also responsible for the stimulation of PLA₂ and elevation of intracellular calcium caused by arachidonic acid-regulated Ca²⁺-permeable (ARC) channels. Additionally, there is a potent store-operated Ca²⁺ entry (SOC) in cardiomyocyte. Negative (NPS 2143) and positive (R 568) allosteric modulators of CaSR recapitulate effects of low and high agmatine doses on Ca²⁺ handling and NO synthesis. These facts and the alteration of agmatine influence in response to an increase of extracellular Ca²⁺, which is the direct agonist of CaSR, may confirm the participation of CaSR in regulation of Ca²⁺ handling and excitability of cardiomyocytes by agmatine.

真正的冬眠者是哺乳动物的非凡群体，其心脏对诸如深低温，局部缺血，心律不齐等压力产生抵抗力。冬眠物种的心肌细胞有效地控制玉米粥期间钙^{离子2 +}稳态的能力的研究很少。对这些机制的更好的理解可以允许引入改善心脏性能的新策略，并且可能对心血管医学有用。在这里，我们首次表明内源性神经递质胍丁胺对Ca ²⁺处理的调节，进而对心肌细胞的收缩性的调节，是通过调节钙敏感受体（CaSR）来实现的。在冬眠松鼠的离体心肌细胞中产生稳定的Ca ²⁺在没有实际肌细胞兴奋的情况下发生短暂的瞬变，低剂量的这种多胺（最高500μM）会诱导PI ₃激酶的_Gβγ依赖性活化，并随后通过内皮NO-刺激Akt激酶和一氧化氮（NO）的产生。合酶（eNOS）。由于肌（内）质Ca ²⁺ ATPase（SERCA）增强了Ca ^2+的再摄取，因此NO的产生消除了Ca ^2+的振荡。同时，发生磷脂酶A ₂（PLA ₂）的活化和花生四烯酸依赖性Ca ^2+的进入，从而补充了Ca ²⁺店铺。高浓度的胍丁胺（> 2 mM）诱导其他CaSR介导的途径，包括磷脂酶C（PLC）途径，肌醇三磷酸（IP ₃）和双酰基甘油（DAG）的形成，然后诱导其靶标：IP ₃受体和蛋白激酶C异构体（PKC）。此外，它还负责刺激由花生四烯酸调节的Ca ²⁺渗透性（ARC）通道引起的PLA ₂和细胞内钙的升高。此外，心肌细胞中存在有效的存储操作性Ca ²⁺进入（SOC）。CaSR的负（NPS 2143）和正（R 568）变构调节剂概括了低剂量和高剂量胍丁胺对Ca ^2+的影响处理和NO合成。这些事实以及响应于胞外Ca ²⁺增加的胍丁胺影响的变化，Ca ²⁺是CaSR的直接激动剂，可能证实CaSR参与了胍基丁胺对Ca ²⁺处理和心肌细胞兴奋性的调节。