Gap junctions consist of an array of densely packed transmembrane channels that provide direct cell‐to‐cell communication. Gap junctions are widely distributed and contribute to multiple functions of cells from coordinating heartbeat, to insulin secretion, to neurological functions. Their importance for the coordination of multi‐cellular live is supported by the large number of existing connexins (the gap junction proteins) with 21 different members expressed in humans alone. Connexin43 is the most widely distributed and best studied connexin protein. Gap junction channels consist of two half or hemi‐channels (termed connexons), each provided by one of two neighboring cells that dock head‐on to form the complete, two plasma membranes spanning gap junction channel. While we know well how gap junctions form, the field still struggles to explain how and where the first connexons dock. Apparently, some helper proteins are necessary. As gap junctions have been found in the vicinity of tight and adherens junctions, one concept postulates that these junctions reduce the nominal distance of plasma membranes, and thus allow connexons to interact and dock. In article 2000031 of this issue, Fritz Rathjen presents novel and exciting evidence suggesting that CAR and CAR‐family members (BT‐IgSF, CLMP, ESAM) regulate gap junction function and indeed may aid in connexon docking.^[1] CAR stands for Coxsackie and Adenovirus Receptor, transmembrane proteins of the Ig‐like cell adhesion protein superfamily that provide cell‐cell adhesion via homophilic binding. They received their name as coxsackie, and adenoviruses use the protein as a receptor and to somehow move directly from cell to cell.^[2] CAR and CAR family members have been postulated to function in tight junction regulation. However, as knockdown of individual CAR family members has no significant effect on tight junction function and integrity, yet changes in the localization, expression intensity and phosphorylation of gap junction connexins were consistently detected in knockouts of CAR, CLMP or BT‐IgSF family members, the author speculates that CAR, and CAR family members may instead represent regulators of gap junctions. His hypothesis is based on a number of biological findings where CAR members, tight, and gap junctions are located in close proximity, as e.g. in the blood/brain and blood/testes‐barrier and in the intercalated discs of heart myocytes. That CAR and CAR family members could aid connexon docking is an appealing concept, as CAR closely localizes to gap junctions,^{[3, 4]} forms transmembrane adhesions, and functions in direct cell‐to‐cell virus transmission.^[2] Moreover, all CAR members harbor a class 1 PDZ (PSD‐95/Disc‐large/ZO‐1) recognition motif in their cytoplasmically located C‐terminal domain. We know that a plethora of proteins including the scaffolding protein ZO‐1 (zonula occludens‐1 which binds to most connexins via its PDZ‐2 domain), phosphatases, kinases, ubiquitinases and cytoskeletal proteins (drebrin/actin, microtubules) interact with connexins during all stages of the gap junction live cycle from biosynthesis, to functional regulation, to endocytosis and degradation^{[5, 6]}; however no experimentation has provided conclusive evidence that would pinpoint a protein or mechanism to connexon docking. Thus, it is tempting to speculate that ZO‐1 could interact with CAR (via its PDZ‐domain 1) and connexin proteins (via its PDZ domain 2) to facilitate connexon docking. Future research should reveal whether CAR and CAR family members represent the long searched after proteins that allow initial gap junction connexons to dock, or what other role they might play in gap junction regulation. No matter what role CAR and CAR family members play in gap junction function, it ought to be explored.

间隙连接由一系列密集的跨膜通道组成，这些通道提供直接的细胞间通讯。间隙连接分布广泛，有助于细胞的多种功能，从协调心跳到胰岛素分泌，再到神经功能。它们对于协调多细胞生命的重要性得到了大量现有的连接蛋白（间隙连接蛋白）的支持，其中仅在人类中就表达了 21 个不同的成员。连接蛋白 43 是分布最广、研究最好的连接蛋白。间隙连接通道由两个半通道或半通道（称为连接ons），每个由两个相邻细胞中的一个提供，这些细胞正面对接以形成完整的两个跨越间隙连接通道的质膜。虽然我们很清楚间隙连接是如何形成的，但该领域仍然难以解释第一个连接子如何以及在何处停靠。显然，一些辅助蛋白是必要的。由于在紧密连接和粘附连接附近发现了间隙连接，一个概念假设这些连接减少了质膜的标称距离，因此允许连接子相互作用和对接。在本期的第 2000031 篇文章中，Fritz Rathjen 提出了新颖而令人兴奋的证据，表明 CAR 和 CAR 家族成员（BT-IgSF、CLMP、ESAM）调节间隙连接功能，并且确实可能​​有助于连接子对接。^{[ 1 ]}CAR 代表柯萨奇和腺病毒受体，是 Ig 样细胞粘附蛋白超家族的跨膜蛋白，通过同源性结合提供细胞间粘附。他们的名字叫柯萨奇，腺病毒使用这种蛋白质作为受体，并以某种方式直接从一个细胞移动到另一个细胞。^{[ 2 ]}CAR 和 CAR 家族成员被假定在紧密连接调节中起作用。然而，由于个别 CAR 家族成员的敲除对紧密连接功能和完整性没有显着影响，但在 CAR、CLMP 或 BT-IgSF 家族成员的敲除中始终检测到间隙连接蛋白的定位、表达强度和磷酸化的变化，作者推测 CAR 和 CAR 家族成员可能反而代表了间隙连接的调节器。他的假设基于许多生物学发现，其中 CAR 成员、紧密连接和间隙连接非常接近，例如在血液/大脑和血液/睾丸屏障以及心肌细胞的闰盘中。CAR 和 CAR 家族成员可以帮助 connexon 对接是一个吸引人的概念，^{[ 3, 4 ]}形成跨膜粘附，并在直接的细胞间病毒传播中发挥作用。^{[ 2 ]}此外，所有 CAR 成员在其位于细胞质的 C 末端结构域中都含有 1 类 PDZ (PSD-95/Disc-large/ZO-1) 识别基序。我们知道大量蛋白质，包括支架蛋白 ZO-1（zonula occludens-1，通过其 PDZ-2 结构域与大多数连接蛋白结合）、磷酸酶、激酶、泛素酶和细胞骨架蛋白（drebrin/actin、微管）与连接蛋白相互作用在间隙连接生命周期的所有阶段，从生物合成到功能调节，再到内吞作用和降解^{[ 5, 6 ]}; 然而，没有实验提供确凿的证据来确定连接子对接的蛋白质或机制。因此，很容易推测 ZO-1 可以与 CAR（通过其 PDZ 结构域 1）和连接蛋白（通过其 PDZ 结构域 2）相互作用以促进连接子对接。未来的研究应该揭示 CAR 和 CAR 家族成员是否代表了长期寻找的允许初始间隙连接连接子对接的蛋白质，或者它们在间隙连接调节中可能发挥的其他作用。无论 CAR 和 CAR 家族成员在间隙连接功能中发挥什么作用，都应该进行探索。