Gap Junction

1. Gap Junction M.A. Ahmadi-Pajouh

2. Non Synaptic Cell-Cell Junctions: • Intermediate Junction • Desmosome • Gap Junction: • Local circuit current • Depolarization of the adjacent resting cell

4. 20 Angstrom in diameter • Molecules < 1000 daltons (750 daltons=1 angstrom= 1.0E-10 meter) Low Resistance • Resistance: • Ca+ • pH • Electric Fields • Sodium concentration

5. Electrical coupling via gap junctions is extremely important in the brain and for functioning of the heart (myocardium). Connexin-43 (Cx43) knock-out mice die early from heart misformations. Cell-cell channel connectivity is crucial for normal hearing, and mutations in Cx26 course non-syndromic deafness.

6. In nonexcitable cells, such as liver or lens cells, gap junctions mediated an exchange of metabolites which is vitally important, and mutations in Cx46 and Cx50 have been shown to be responsible for congenital cataracts. Charcot-Marie-Tooth disease is linked to mutations in Cx32 gene, which is expressed in liver and oligodendrocytes.

7. Cardiac cells • Colatsky and Tsien: Electrical continuity of neighboring cardiac cells:

8. Results • Behaves like a single uniform cell • Time constant=18 msec • Total intercellular resistivity =350 ohm cm = Low Intercellular Resistance

9. Chapman and Fry: • ventricular trabeculea from frog ventricle • 6 different axial positions • Results: • Lambda= 0.328 • Thaw=4.15 msec • Total intercellular resistivity =588 ohm cm • Cytoplasmic Resistivity = 282 ohm cm • Remaining = 306 ohm cm

10. Cell: • Length 131 micrometer • Radius 7.5 micrometer • So, Lumped junctional resistance per cell = 2.2 M ohms • So, Specific junctional resistance = 4 ohm cm^2 • BUT resting membrane resistance= 2500 ohm cm^2 (*2 for two cells)

11. Results: • Cardiac intracellular space is electrically interconnected. • Activation in one part of tissue continuous contiguously to all surrounding tissue.

12. Newer Data • Patch Clamp • Enzymatic technique for isolating cardiac cells

17. I1 – V1 is linear over a range -+40 mv • So rn is resistive • rn=3.25 Mega ohms • This independent of the pulse duration

19. In 1877, Engelmann [2] reported that cardiac cells in direct contact with each other during life became independent as they died. This phenomenon, named ‘‘healingover’’, was believed to result from the formation of ionic barriers between injured and uninjured cells.

20. Almost a century later, De´le`ze reported that cut heart fibers do not heal in the absence of external Ca2 +, but do so rapidly when Ca2 + is supplied. This provocative observation, published soon after the serendipitous discovery that most cells communicate directly with each other electrically and metabolically

21. Ca2+ role is obvious in • amphibian embryonic cells [20], • rat lacrimal cells [21], • crayfish giant axons[22,23], • Novikoff hepatoma cells [24,25], • astrocytes [26–28], • lens cultured cells [29], • pancreatic h-cells and acinar cells [30–32], • osteoblasts [33], • cochlear supporting cells [34,35]

22. This suggests that an increase in [Ca2 +]i rapidly closes gap junction channels to complete cell–cell uncoupling. However, • the possibility that Ca2 + was buffered so rapidly that it was unable to reach the junctional area cannot be discarded.

23. Imaging of intracellular transport of Connexin43-GFP. Connexin-43 travels from the ER through the Golgi and is targeted to the plasma membrane at cell-cell interfaces where it forms gap junction channels

24. These gap junction subunits are transported anterogradely from the ER to the plasma membrane (PM) and stabilized there to form cell-cell channels. • Electrical synapses important for the generation of synchronous oscillations are thought to be mediated by neuronal gap junctions.

25. Recent Studies • The role of myoendothelial gap junctions in the formation of arterial aneurysms • Synchronization of chaotic neurons coupled with gap junction with time delays in external electrical stimulation

26. Recently, a new important class of gap junction proteins has been recognized in vertebrates, the pannexins (Panxs; Panchin et al., 2000), which are considered homologous to the innexins of the invertebrates.

27. Also in Facilitation of the Damage • Effective Reduction of Neuronal Death by Inhibiting Gap Junctional Intercellular Communication in a Rodent Model of Global Transient Cerebral Ischemia • One decisive key step in understanding why an ischemic insult gradually expands may be to establish how gap junction channels permit dying cells in the ischemic focus to communicate, in particular, with viable cells.

28. ictal seizures • There is evidence that not only chemical synapses, but also direct electrical coupling of the neuronal/glial system participates via gap junction (GJ) channels in the normal and abnormal physiologic rhythms . • The intercellular communication provided by GJ channels is involved both in the physiological synchronization and in the pathological hypersynchrony. • This could be one of the basic elements of the epileptic processes demonstrated by various in vitro and in vivo epilepsy models.

29. 2008 paper on Seizure • A key role for electrical communication between cortical bursting interneurons during ictal seizures was hypothesized in the 4-aminopyridine (4-AP) in vivo epilepsy model • The blockade of GJ communication has been shown to reduce seizure activity in a number of epilepsy models in vitro