电压门控钠通道(VGSC)是跨膜蛋白复合物,对神经和肌纤维中动作电位的产生和传播至关重要。典型的VGSC通常被认为是由两类跨膜亚基-α-亚基(孔形成)和两个β-亚基(非孔形成)形成的异源三聚体复合物。NaV1.5是哺乳动物心室的主要钠通道α亚基,其他α亚基的含量较低,包括NaV1.6,在场。有四个β亚基,β1-β4,由四个基因编码,SCN1B-SCN4B,每个都在心脏组织中表达。最近的研究表明,除了渠道门控和贩运方面的任务之外,Scn1b的产物可能在心脏动作电位传导和细胞内信号传导中具有新的作用。这包括证据表明,β亚基胞外氨基末端结构域促进了插入的椎间盘中的粘附相互作用,并且其羧基末端区域是受调节的膜内蛋白水解(RIP)信号通路的底物-由β1RIP产生的羧基末端肽转运到细胞核并改变各种基因的转录,包括Nav1.5。除β1外,Scn1b基因还编码可变剪接变体,β1B,它含有与β1相同的细胞外粘附域,但具有独特的羧基末端。虽然β1B通常被认为是分泌型变体,证据表明,当与NaV1.5共表达时,它保持在细胞膜上,提示这种未被研究的蛋白质的潜在独特作用。在这次审查中,我们专注于已知的由Scn1b在心脏中编码的两个β亚基变体,特别关注最近的发现和这一新信息提出的问题。我们还探索了表明β1和β1B可能是新型抗心律失常疗法的有吸引力的靶标的数据。
Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by two classes of membrane-spanning subunit-an α-subunit (pore forming) and two β-subunits (non-pore forming). NaV1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including NaV1.6, being present. There are four β-subunits, β1-β4, encoded by four genes, SCN1B-SCN4B, each of which are expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the β-subunit extracellular Amino-terminal domain facilitates adhesive interactions in intercalated discs and that its Carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway-with a Carboxyl-terminal peptide generated by β1 RIP trafficked to the nucleus and altering transcription of various genes, including NaV1.5. In addition to β1, the Scn1b gene encodes for an alternative splice variant, β1B, which contains an identical extracellular adhesion domain to β1, but has a unique Carboxyl-terminus. Whilst β1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with NaV1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known on the two β-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate β1 and β1B may be attractive targets for novel anti-arrhythmic therapeutics.