The transient receptor potential (TRP; C-classical, TRPC) channel TRPC3 allows a cation (Na+/Ca2+) influx that is favored by the stimulation of Gq protein-coupled receptors (GPCRs). An enhanced TRPC3 activity is related to adverse effects, including pathological hypertrophy in chronic cardiac disease states. In the present study, we identified FK506-binding protein 52 (FKBP52, also known as FKBP4) as a novel interaction partner of TRPC3 in the heart. FKBP52 was recovered from a cardiac cDNA library by a C-terminal TRPC3 fragment (amino acids 742-848) in a yeast two-hybrid screen. Downregulation of FKBP52 promoted a TRPC3-dependent hypertrophic response in neonatal rat cardiomyocytes (NRCs). A similar effect was achieved by overexpressing peptidyl-prolyl isomerase (PPIase)-deficient FKBP52 mutants. Mechanistically, expression of the FKBP52 truncation mutants elevated TRPC3-mediated currents and Ca2+ fluxes, and the activation of calcineurin and the nuclear factor of activated T-cells in NRCs. Our data demonstrate that FKBP52 associates with TRPC3 via an as-yet-undescribed binding site in the C-terminus of TRPC3 and modulates TRPC3-dependent Ca2+ signals in a PPIase-dependent manner. This functional interaction might be crucial for limiting TRPC3-dependent signaling during chronic hypertrophic stimulation.

中文翻译：

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FKBP52调节依赖TRPC3的Ca2 +信号和心肌细胞培养物的肥大生长。

瞬时受体电势（TRP; C-classical，TRPC）通道TRPC3允许阳离子（Na + / Ca2 +）流入，这受到Gq蛋白偶联受体（GPCR）的刺激。TRPC3活性增强与不良反应有关，包括慢性心脏病状态下的病理性肥大。在本研究中，我们确定了FK506结合蛋白52（FKBP52，也称为FKBP4）是TRPC3在心脏中的新型相互作用伴侣。在酵母双杂交筛选中，通过C端TRPC3片段（氨基酸742-848）从心脏cDNA文库中回收了FKBP52。FKBP52的下调促进新生大鼠心肌细胞（NRCs）的TRPC3依赖性肥大反应。通过过表达肽基-脯氨酰异构酶（PPIase）缺陷的FKBP52突变体可以达到类似的效果。机械上，FKBP52截断突变体的表达增加了TRPC3介导的电流和Ca2 +通量，以及钙调神经磷酸酶的活化和NRC中活化T细胞的核因子。我们的数据表明FKBP52通过TRPC3的C端中尚未描述的结合位点与TRPC3缔合，并以PPIase依赖性方式调节TRPC3依赖性Ca2 +信号。这种功能性相互作用对于限制慢性肥大性刺激过程中限制TRPC3依赖性信号传导可能至关重要。