1 Medicina (Kaunas) 2010; 46(1) Diversity and properties of connexin gap junction channels Mindaugas Račkauskas, Vaidas Neverauskas, Vytenis Arvydas Skeberdis Institute of Cardiology, Kaunas University of Medicine, Lithuania Key words: connexins; connexons; gap junction channels; structure; function. Summary. Gap junction channels are composed of two apposing hemichannels (connexons) in the contiguous cells and provide a direct pathway for electrical and metabolic signaling between adjacent cells. The family of connexin genes comprises 20 members in the mouse and 21 genes in the human genome. Connexins are expressed in all tissues except differentiated skeletal muscle, erythrocytes, and mature sperm cells. Various tissues express more than one type of connexins; therefore, homotypic, heterotypic, and heteromeric gap junction channels may form between cells. In this article, we briefly review basic gating and permeability properties of homotypic and heterotypic gap junction channels as well as recent achievements in the research of their regulation by transjunctional voltage, intracellular calcium, pH, and phosphorylation. REVIEWS Correspondence to V. A. Skeberdis, Institute of Cardiology, Sukilėlių 17, 50161 Kaunas, Lithuania. E-mail: arske@med.kmu.lt Families of gap junction proteins Gap junction (GJ) channel proteins are subdivided into three families: innexins, pannexins, and connexins (1–3). Innexins are expressed in protostomes, while connexins and pannexins have been identified in deuterostomes. Pannexins have no homology with connexins and share 20% homology with innexins. All these proteins have four alpha helical transmem- brane domains (M1–M4), intracellular N- and C-ter- mini, two extracellular loops (E1, E2), and a cyto- plasmic loop (I1) (4–6) (Fig. 1). Six innexin/pannexin/connexin subunits form a hemichannel (innexon/pannexon/connexon). The presence of cysteine residues in the extracellular loops is critical for gap junction formation by two apposing Fig. 1. Topological model of a connexin Connexins, as well as pannexins and innexins, possess four transmembrane domains (M1–M4), intracellular N- and C-termini, two extracellular loops (E1–E2) and one intracellular loop (I1) hemichannels in contiguous cells. Connexins and innexins possess 3 or 2 cysteines in each extracellular loop, respectively, and form hemichannels and gap junction channels. The pannexins contain 2 cysteines in each extracellular loop; however, glycosylation of extracellular loops and protein in general precludes formation of functional gap junction channels (7). In that way, pannexins most likely form only nonjunc- tional channels and play paracrine role releasing ATP or glutamate into extracellular space and uptaking certain membrane-impermeant molecules into cells (8, 9). In contrast to connexin-based gap junctions, innexin-based channels are sensitive to membrane potential, closing with depolarization (10). Structure of connexin gap junction channels GJ channels provide a direct pathway for electrical and metabolic signaling between adjacent cells (11– 14). The family of connexin (Cx) genes consists of 20 members in the mouse and 21 genes in the human genome. hCx25, hCx59 occur only in the human genome and mCx33 only in the mouse genome. Also, unusual Cx23 with four instead of six cysteine residues in its two extracellular loops was identified in the mouse (15, 16). All other genes are orthologous pairs. Connexins are named by their molecular mass within the range of 23–62 kDa. For example, Cx30 molecular mass is 30366 Da, Cx43 – 43036 Da. A gap junction channel pore is approximately 100–150 Å in length and 12.5 Å in width with a 20 Å gap between conti- guous cells. A single GJ channel is formed by stable, noncovalent interactions of two hemichannels located Adresas susirašinėti: V. A. Skeberdis, KMU Kardiologijos insti- tutas, Sukilėlių pr. 17, 50161 Kaunas. El. paštas: arske@med.kmu.lt