Transcript Gap Junction

Gap Junction
M.A. Ahmadi-Pajouh
• Non Synaptic Cell-Cell Junctions:
– Intermediate Junction
– Desmosome
– Gap Junction:
• Local circuit current
• Depolarization of the adjacent resting cell
• 20 Angstrom in diameter
• Molecules < 1000 daltons
(750 daltons=1 angstrom= 1.0E-10 meter)
Low Resistance
– Resistance:
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Ca+
pH
Electric Fields
Sodium concentration
• 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.
• 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.
Cardiac cells
• Colatsky and Tsien:
Electrical continuity of neighboring cardiac
cells:
Results
• Behaves like a single uniform cell
• Time constant=18 msec
• Total intercellular resistivity =350 ohm cm
= Low Intercellular Resistance
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
• 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)
• Results:
– Cardiac intracellular space is electrically
interconnected.
– Activation in one part of tissue continuous
contiguously to all surrounding tissue.
Newer Data
• Patch Clamp
• Enzymatic technique for isolating cardiac
cells
• I1 – V1 is linear over a range -+40 mv
• So rn is resistive
• rn=3.25 Mega ohms
• This independent of the pulse duration
• 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.
• 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
Ca2+ role is obvious in
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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]
• 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.
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
• 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.
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
• 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.
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.
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.
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