Innexin Gap Junctions

Introduction to gap junctions

Gap junction mediated intercellular communication

Illustration of cells containing gap junction holochannels and hemichannels

Figure legend: Diagram of cells endowed with gap junction channels. A, Cells 1+2 can communicate by directly exchanging small molecules such as cAMP, cGMP, Ca+ and K+ (green arrows, dots) via a 'classical' arrangement of gap junctions (GJ) (holochannels in a plaque). B, Cell 3 has undocked hemichannels in the plasma membrane. Undocked hemichannels were thought to exist in a closed state until they docked to hemichannels in a neighbouring cell - presumably to prevent disruption of cellular homeostasis. Relatively recently it was discovered that hemichannels in the plasma membrane can be found in an open state. Open hemichannels allow small signalling molecules (green dots eg, ATP) to be released into the extracellular space where they can bind to, and activate, nearby receptors (red)(Romanov et al, 2007, Dando and Roper, 2009). Hence, cells 3+4 can communicate using a mix'n'match version of gap junction+ligand/receptor signalling. C, Innexin proteins have been detected in the nucleus of certain cell types (Ostrowski et al, 2008) but their role there has not been explored. It has been proposed that connexins might also be able to alter transcription following re-distribution to the nucleus (Dang et al. 2003)...although the only evidence is based on connexin fragments, so far.

Gap junction channel structure

Diagram showing connexin-based holo- and hemi-channels at the intercellular junction of two cells
Illustration of gap junction channels in the plasma membrane. Based on Cx channels

click image-box for full image in PDF format

Figure legend: Diagram of a gap junction composed of vertebrate connexin subunits. Invertebrate innexin subunits are believed to form channels with a similar overall structure (although there is virtually no available data supporting this). A single gap junction channel (holochannel) is composed of two hemichannels, one contributed from each of the docked cells. Each hemichannel is comprised of six connexin gap junction subunits (innexin subunits in the case of invertebrates). The hydrophilic holochannel pore allows passage of small molecules such as ions and second messengers directly from cell to cell. Holochannels can accumulate at distinct regions of the plasma membrane forming specialized 'plaque' structures (Plaques in salivary gland cells).

Intercellular communication is essential for the normal development of multicellular animals. Ligand/receptor and gap junction signalling are the two main mechanisms permitting cell-cell communication to take place. An understanding of gap junction mediated communication and its interaction with ligand/receptor pathways is therefore crucial for constructing an accurate model of development in normal and diseased tissues. Three distinct gap junction-forming protein families have been identified: Connexins (Cx) (Evans and Martin 2002), Pannexins (Px) (Bruzzone et al. 2003, Panchin et al. 2000) and Innexins (Inx) (Phelan et al. 1998). Connexin-based gap junctions have received the most research attention as they are present in vertebrates and underlie a number of human pathologies (Alldredge 2008). Connexins are not found in invertebrates where the role of gap junction signalling is mediated by members of the innexin protein family (Innexin family description). A brief compare-and-contrast table is provided below.

Brief summary table comparing connexins (Cx), pannexins (Px) and innexins (Inx)
Observation Cx Px Inx Notes and references
Required for gap junction-mediated intercellular communication Cx: Kumar and Gilula 1996. Px: Bruzzone et al. 2003
Inx: Phelan et al. 1998.
Form hemichannels ? Cx: Spray et al. 2006. Px: Huang et al. 2007.
Role in cell adhesion? ? ? Cx: Prochnow and Dermietzel 2008 and Cotrina et al. 2008.
Evidence of communication or cross-talk with ligand/receptor pathways? Cx: Hirschi et al. 2003. Px: Pelegrin and Surprenant, 2006.
Inx: Lechner et al. 2007.
Structure and distribution
Found in vertebrates No connexins have been identified in invertebrate genomes so far.
Found in invertebrates However, innexins and pannexins may be descendants from a common ancestor. In which case innexins are present in vertebrates...but the important question then becomes - do the related family members participate in the same biological functions/pathways in vertebrates and invertebrates.
Extensive tissue distribution Cx: Beyer et al. 1989. Px: Bruzzone et al. 2003
Inx: Stebbings et al. 2002
Four predicted transmembrane domains Cx: Rahman and Evans, 1991. Px: Penuela et al. 2007.
Inx: Starich et al. 1996
Intracellular amino- and carboxy- termini The protein termini have been proposed to have diverse roles including channel regulation (Oshima et al. 2007) and plaque formation ((Martinez et al. 2003).
Number of conserved Cysteines in each extracellular loop 3* 2 2* The conserved cysteine residues are essential for cognate hemichannels to dock and form holochannels. Bao et al. 2004.
Can form heteromeric channels ? Cx: Weber et al. 2004. Inx: Lehmann et al. 2006
Interact with molecular components of other cell junction structures ? Cx: Giepsmans et al. 2001 Inx: Bauer et al. 2004

* A protein with homology to connexins was reported that possessed only 2 extracellular cysteine residues in the extracellular domains (Iovine et al. 2008) and Inx4 is unique amongst the innexins for possessing three extracellular cysteines (see zpg/Inx4 summary).

This is the end of the Innexins introduction section

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