Second Messengers
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Second Messenger Systems

fig 6.25

Fig 6.25 General Mechanism of Second Messenger Action.

Second messengers are intracellular molecules or ion that are regulated by extracellular signaling agents such as neurotransmitters and hormones (first messengers).

Second messengers typically operate by activating protein kinases that phosphorylate carious target proteins, thereby altering the functioning of these proseins. Such functional effects are subsequently reversed by protein phosphotase-mediated dephosphorylation.

Second messengers modulate a wide range of both rapid and long-term neuronal processes.

fig 6.26

Fig 6.26 Synthesis of Cyclic AMP.

Adenylyl cyclase converts adenosine triphosphate (ATP) into cyclic AMP. Phosphodiesterase converts cAMP into the inert compound 5’ –AMP. Cyclic GMP undergoes similar reactions but guanine is substituted for the adenine moiety.

fig 6.27

Fig 6.27 Structure and Mechanism of Adenylyl Cyclase and cAMP-Dependant Protein Kinase A (PKA).

Adenylyl cyclase is a membrane glycoprotein possessing a total of 12 transmembrane domains (depicted as lines passing through the membrane) and two catalytic domains (CAT) within the cytoplasm.

This enzyme converts ATP to cAMP upon stimulation by the a subunits of G_s. In the inactive state, PKA is a complex of two catalytic subunits (C) bound to two regulatory subunits (R) that inhibit catalytic activity.

When two molecules of cAMP bind to each of the regulatory subunits, the catalytic subunits dissociate from the complex and are free to phosphorylate various target proteins.

fig 6.28

Fig 6.28 Synthesis of Nitric Oxide

fig 6.29

Fig 6.29 Intercellular Signaling by Nitric Oxide.

The first step in NO signaling is an elevation of cytoplasmic Ca²⁺ levels by thi opening of ligand- or voltage-gated Ca²⁺ channels. This causes the generation of NO from the amino acid L-arginine (L-Arg) by the Ca²⁺-activated enzyme nitric oxide synthase. NO then diffuses out of the generator cell to target cells, where it stimulates cGMP synthesis by soluble guanylyl cyclase.

fig 6.30

1. The anatomy of a vertebrate rod. In the absence of light, the rod membrane is partially depolarized due to an open cation channel. The disc membrane (shown magnified at the upper right) contains high concentrations of the rod photopigment rhodopsin (Rh), the G protein transducin (G_t), and a cGMP phosphodiesterase (PDE).
2. Absorption of light (hn ) by Rh initiates a cascade involving activation of G_t, stimulation of PDE, and cation channel closing due to the rapid reduction in cGMP levels. These events cause membrane hyperpolarization and a reduction in transmitter (glutamate) release by the rod.

fig 6.31

1. In the absence of Ca²⁺/calmodulin (CaM), the active site of CaM-K II (kinase domain) is inhibited by binding of the inhibitory domain.
2. Binding of CaM to its recognition site alters the enzyme’s conformation, leading to phosphorylation of substrate proteins, including CaM-K II itself (this occurs at a threonine residue at position 286).
3. When the intracellular Ca²⁺ level falls, CaM dissociates from the enzyme; however, the phosphorylated threonine prevents reassociation of the inhibitory domain with the active site. Kinase activity is now partially independent of Ca²⁺ (the "switch" is on).
4. Autophosphorylation my now occur at a site within the CaM binding domain, which causes the enzyme to be completely insensitive to CaM. Finally, CaM-K II is dephosphorylated by phosphatases, returning to its inactive state.

fig 6.32

Fig 6.32 Formation and Action of Second Messengers Derived from PIP₂

PIP₂ is a membrane phospholipid that can be hydrolyzed by two different forms of phospholipase C (PLC), one coupled to certain G proteins and the other activated by neurotrophin-stimulated protein tyrosine kinase (PTK) receptors.

PIP₂ hydrolysis liberates two second messengers, diacyglycerol (DAG) and inositol triphosphate (IP₃). DAG remains in the membrane, where it stimulates protein kinase C (PKC). IP₃ diffuses into the cytoplasm, where it releases Ca²⁺ from the endoplasmic reticulum by binding to a specific receptor on the ER membrane.

The Ca²⁺ concentration is typically in the millimolar range (10^-3 M) outside of the plasma membrane, but much lower (10^-8-10^-7 M) in the cytoplasm. Release of Ca²⁺ from the ER can elevate intracellular concentration to a range (10^-7-10^-6 M) that activates Ca²⁺-dependant processes.

fig 6.33

Fig 6.33 Eicosanoide that Participate in Arachidonic Acid-Mediated Signaling.

Following its release from membrane phospholipids, arachidonic acid (AA) is converted to a number of biologically active compounds by the enzyme cyclooxygenase, cytochrome P-450, and lipoxygenase. It can also be converted to hydroperoxy acid by nonenzymatic autooxidation. These compounds, which are collectively called eicosanoids, function as second or third messengers in AA signaling systems.