cAMP CAN BE VIEWED AS SUBSERVING TWO
MAJOR FUNCTIONS IN THE NERVOUS SYSTEM
AND MOST OF THE EFFECTS OF cAMP ON
CELL FUNCTION ARE MEDIATED VIA PROTEIN
PHOSPHORYLATION
First, cAMP mediates some short-term aspects of
synaptic transmission: some rapid actions of certain
neurotransmitters on ion channels that do not involve
ligand-gated channels are mediated through cAMP.
Second, cAMP, along with other intracellular messengers,
plays a central role in mediating other aspects of
synaptic transmission: virtually all other effects of
neurotransmitters on target neuron functioning,
both short-term and long-term, are achieved through
intracellular messengers. This includes regulation of the
general metabolic state of the target neurons, as well
as modulatory effects on neurotransmitter synthesis,
storage, release and receptor sensitivity; cytoskeletal
organization and structure; and neuronal growth and
differentiation. This also includes those long-term
actions of neurotransmitters that are mediated through
alterations in neuronal gene expression.
membrane depolarization and more slowly to increases
in cellular levels of cAMP by activation of Ca2+/
calmodulin-sensitive forms of adenylyl cyclase. cAMP
then mediates several other effects of glutamate on the
neurons. By virtue of numerous interactions between
cAMP and other intracellular messenger pathways, these
pathways play the central role in coordinating a myriad
neuronal processes and adjusting neuronal function to
environmental cues [43].
It is important to emphasize that such a role for cAMP
and other intracellular messengers is not limited to
actions of neurotransmitters mediated via G proteincoupled
receptors. Thus, although activation of ligandgated
ion channels leads to initial changes in membrane
potential independent of intracellular messengers,
it also leads to numerous additional, albeit slower,
effects that are mediated via intracellular messengers.
For example, activation of certain glutamate receptors,
which are ligand-gated ion channels, leads rapidly to
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THE CLAPPER 2015 - 2016
By far the most important mechanism by which cAMP
exerts its myriad physiological effects is through the
specific activation of cAMP-dependent protein kinase.
This was demonstrated first by Krebs and coworkers for
cAMP regulation of glycogenolysis, and shortly thereafter
it was shown to be a widespread mechanism by Paul
Greengard and his colleagues. Indeed, cAMP-dependent
protein kinase is now known to phosphorylate virtually
every major class of neural protein; this accounts for the
ability of cAMP to influence so many diverse aspects
of neuronal function. The ability of cAMP to activate
protein kinases and the role of protein phosphorylation
in the regulation of neuronal function are covered.
Specificity is achieved at two levels: at the level of tissuespecific
receptors for the neurotransmitter or hormone
and at the level of tissue-specific substrate proteins for
the protein kinase. Only tissues which possess specific
receptors will respond to a certain neurotransmitter or
hormone. Moreover, since all cells contain very similar
catalytic subunits of cAMP-dependent protein kinase,
the nature of the proteins that are phosphorylated in