Chemistry Reference
In-Depth Information
neuronal excitability, setting the threshold for action potential initiation and propagation to the dendritic and
axonal compartments. Na
v
1.2 is predominantly expressed in unmyelinated axons, where it conducts action
potentials. Na
v
1.6 is prominently found at nodes of Ranvier, where it propagates action potentials, and, at axon
initial segments where action potentials initiate. Modulation of Na
v
1 currents is undoubtedly important in vivo,
and mutations that subtly alter Na
v
1 channel function can lead to human diseases of hyperexcitability such as
epilepsy.
Calcium channels (Ca
v
channels) mediate calcium influx in neuronal cells in response to membrane depo-
larisation, mediating a wide range of intracellular processes such as activation of calcium-dependent enzymes,
gene transcription, and neurotransmitter exocytosis/secretion. Their activity is an essential requirement for the
coupling of electric signals in the neuronal plasma membrane to physiological events within the cells.
Biochemical characterisation of native brain Ca
v
channels revealed that, in addition to the large principal
a
1
subunit, there are also numerous auxiliary subunits. The
a
1
subunit is the largest and principal subunit,
containing the ion conduction pore, the membrane voltage-sensor, and gating apparatus. A number of different
a
1
subunits have been identified and characterised in the mammalian nervous system, each with specific physio-
logical functions and electrophysiological and pharmacological properties.
Calcium and Signal Transduction
Within cells, including nerve cells, fluxes of Ca
2
þ
ions play an important role in signal transduction (Chapter 11).
Most eukaryotic cells export calcium across the plasma membrane or deposit it in membrane-enclosed storage
sites in order to maintain free cytosolic Ca
2
þ
levels at 100
200 nM, roughly 10,000 times less than in the
extracellular space. This allows calcium to function as a second messenger and also as a carrier of biological
signals that guide cells from their origin to their ultimate death. When intracellular Ca
2
þ
increases, the ubiquitous
eukaryotic Ca
2
þ
-binding protein calmodulin binds Ca
2
þ
ions (Chapter 11). This causes a major conformation
change, exposing a previously buried hydrophobic patch on the calmodulin molecule (Figure 11.9), which can
bind to a large number of target enzymes, modifying their activity (Chapter 11).
Ca
2
þ
is also involved in signalling from neuronal synapses to the cell nucleus, resulting in neuronal activity-
dependent control of neuronal gene expression.
3
This synapse-to-nucleus signalling plays a key role in circadian
rhythms, long-term memory, and neuronal survival. The transient rise in free Ca
2
þ
concentration after neuronal
excitation can be transmitted from the cytoplasm to the nucleus in several different ways (
Figure 20.8
). Following
rises in intracellular Ca
2
þ
, the nuclear transcription factor downstream regulatory element antagonistic modulator
(DREAM) is activated. DREAM is abundant in the nucleus and has three Ca
2
þ
-binding motifs, the E
e
F hands
e
=
FIGURE 20.8
Signalling from the membrane to the nucleus: multiple strategies for information transfer. (a) The transcription factors
NFATc4, CREB, and DREAM are all activated following increases in intracellular Ca
2
þ
, yet each relies upon a different mode of information
transfer. At rest, NFATc4 is localised to the cytosol, allowing the transcription factor to be targeted to specific regions of the cell. This would
allow for heightened signalling specificity. Indeed, Ca
2
þ
entry through L-type calcium channels activates this transcription factor preferentially
relative to other voltage-gated Ca
2
þ
channels. Yet, this mode of synapse-to-nucleus signalling is limited in both speed and signal amplification.
Conversely, DREAM can be activated by general rises in intracellular Ca
2
þ
, allowing for rapid information transfer. However, this pathway is
limited in regards to signal specificity. CREB activation is typically initiated by nuclear translocation of the calcium sensor CaM or by an
activating kinase, providing a combination of the advantages found for both NFATc4 and DREAM signalling. (b) A snapshot image of the early
stages (0
e
5 min) of activity-dependent gene expression. Following rises in intracellular Ca
2
þ
, DREAM dissociates from DNA resulting in the
lifting of transcriptional repression. Within seconds of Ca
2
þ
entry through L-type Ca
2
þ
channels and NMDA receptors, CaM translocates to the
nucleus, supporting CREB phosphorylation through the activation of CaMKIV. Nearly as rapid, NFATc4 also undergoes translocation to the
nucleus following its dephosphorylation by calcineurin (CaN). Other pathways outlined in (a), including the MAPK/PKA pathways, subse-
quently begin to exert their influence. Abbreviations, VGCC, voltage-gated calcium channel.
3. Synapses are the local sites of communication between neurons.
