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Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules,
while inhibitory hormone (Ri) is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G protein-linked to stimulative hormone receptor (Rs) and
its subunit upon activation could stimulate the activity of an enzyme or other intracellular
metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone
receptor and its subunit upon activation could inhibit the activity of an enzyme or other
intracellular metabolism.
Cyclic AMP formation
The formation of cyclic AMP can be activated by a very large number of cell stimuli, mainly
neurotransmitters and hormones. All these stimuli are detected by G-protein-coupled receptors
(GPCRs) that use heterotrimeric G proteins , which are the transducers that are responsible for
either activating or inhibiting the enzyme adenylyl cyclase (AC). In the case of AC stimulation,
the external stimulus binds to the GPCR that functions as a guanine nucleotide exchange factor
(GEF) to replace GDP with GTP, which dissociates the heterotrimeric complex into their G
and G subunits. The GSGTP complex activates AC, whereas GiGTP inhibits AC. The G
subunits have GTPase activity that hydrolyses GTP to GDP, thus terminating their effects on
AC. The endogenous GTPase of GSGTP is inhibited by cholera toxin and this causes the
persistent activation of the intestinal fluid secretion that results in the symptoms of cholera.
Adenylyl cyclase (AC)
The large cytoplasmic domains C1 and C2 contain the catalytic region, form a heterodimer and
co-operate with each other to convert ATP into cyclic AMP.
Cyclic AMP signalling effectors
Cyclic AMP is a highly versatile intracellular messenger capable of activating a number of
different effectors.
There are three main effectors of cAMP:
i.
ii.
iii.
specific substrates. Since the RI subunits have a higher cyclic AMP-binding affinity, PKA I will
be able to respond to the lower cyclic AMP concentrations found globally within the bulk
cytoplasm.
Protein kinase A (PKA) II
A characteristic feature of Type II protein kinase A (PKA) is that the regulatory dimer is made
up of RII subunits. Since this RII subunit has a much higher affinity for the A-kinase-anchoring
proteins (AKAPs), PKA II is usually docked to this scaffolding protein and thus has a much
more precise localization to specific cellular targets.
The substrates phosphorylated by cyclic AMP fall into two main groups:
i.
ii.
the cyclic AMP substrates that regulate specific cellular processes and
the cyclic AMP substrates that are components of other signalling systems.
In neurons, cyclic AMP acts through PKA to phosphorylate Ser-845 on the AMPA
receptor
PKA phosphorylates the hormone-sensitive lipase (HLS) that initiates the hydrolysis of
triacylglycerol to free fatty acids and glycerol in both white fat cells and in brown fat
cells.
PKA activates the transcription factor cyclic AMP response element-binding protein
(CREB). This activation is a critical event in the induction of gluconeogenesis in liver
cells.
PKA inhibits the salt-inducible kinase 2 (SIK2) that normally acts to phosphorylate
TORC2, thereby preventing it from entering the nucleus to facilitate the activity of
CREB.
PKA phosphorylates inhibitor 1 (I1), which assists the protein phosphorylation process
by inactivating protein phosphatase 1 (PP1).
PKA contributes to the translocation and fusion of vesicles with the apical membrane
during the onset of acid secretion by parietal cells.
PKA phosphorylates the regulatory (R) domain on the cystic fibrosis transmembrane
conductance regulator (CFTR) to enable it to function as an anion channel.
In kidney collecting ducts, cyclic AMP acts through PKA to phosphorylate Ser-256 on
the C-terminal cytoplasmic tail of aquaporin 2 (AQP2), enabling this water channel to
fuse with the apical membrane to allow water to enter the cell.
Entry of Ca2+ through the L-type CaV1.1 channel (Module 3: Figure CaV1.1 L-type
channel) and the L-type CaV1.2 channel is enhanced through PKA-dependent
phosphorylation.
The cyclic AMP signalling pathway functions in the control of a wide range of cellular
processes:
Cyclic AMP mediates the action of lipolytic hormones in white fat cells by stimulating a
hormone-sensitive lipase.
Heat production by brown fat cells is controlled by noradrenaline acting through cyclic
AMP.