Ch4 SECOND MESSENGERS Flashcards
second messenger
after a ligand binds to its receptor. The drug itself never penetrates the cell
membrane; instead, a second messenger is released to convey the
message to the target
Why do many drugs rely on second messengers?
the ligand cannot penetrate the cell to have a direct effect, because the cell
is surrounded by a lipid membrane. Most drugs are water-soluble
neurotransmitters and are unable to get inside the cell. Thus, to have an
effect internally, something has to take in the water-soluble transmitter
and carry the signal from the surface receptor to the internal structures
of the cell.
signal amplification
The interaction of a few hormones or neurotransmitters (first messengers) can cause the formation of many second messengers. This amplification of the signal occurs because the ligand that stimulates the system causes second messengers to be made constantly until the single ligand molecule detaches. The amplification of the signal is what allows, for example a few micrograms of oxytocin to elicit uterine contractions
Speed of Second Messenger response
The second messenger system is a relatively slow process compared to
the direct altering of cell function, because second messengers have to be
made first
Duration of Second Messenger response
second messengers will persist in the cytoplasm after the original ligand dissociates; thus, the effects will last for some time as well
ligand-gated ion channels
When sodium ion channels are open and sodium rushes in, the membrane
potential increases and becomes less polarized. The decrease in voltage
may open the voltage-sensitive sodium channel, and an action potential
will occur, leading to a muscle contraction or sending a message down an axon. This is a fast process that must be turned on and off instantaneously.
Steroid hormones
are lipophilic and do not need a cell surface receptor because they penetrate the cell directly and interact with the receptors on the hormone response elements
hormone response elements
short sequences of DNA that can bind to hormone receptors and regulate transcription
Thyroid hormones
are lipophilic and very small; they can easily move through the plasma membrane and do not need cell surface receptors.
G Protein
a large protein embedded in a cell membrane.
important because they are the intermediary of many receptors and their effectors, and they can activate or inhibit the manufacture of second messengers.
G Protein–Linked Ion Channel
Do not require second messengers. The receptor has a G protein, which is activated when the ligand binds to the receptor. Once activated, the G protein opens the sodium channel.
G Protein–Coupled Receptors
The receptors that interact with G proteins can be stimulated by ultraviolet light, odorants, hormones, neurotransmitters, and prostaglandins.
G proteins are important because they are the intermediary of many receptors and their effectors, and they can activate or inhibit the manufacture of second messengers
Gs - G protein
stimulates adenylate cyclase
Adenylate cyclase converts adenosine triphosphate (ATP)
into cyclic adenosine monophosphate (cAMP), so Gs leads to more
intracellular cAMP. The cAMP is a second messenger that binds to
receptors inside the cell and activates the inactive protein kinases.
Kinases activate inactive enzymes by adding a phosphate group (PO4
3-). Eventually, cAMP is broken down by phosphodiesterase.
Example - Salbutamol (Ventolin®), also called albuterol (USAN), is a
bronchodilator used in the treatment of asthma. It binds to the β2-
adrenoreceptors, which then activate adenylate cyclase via the Gs protein.
The increase in cAMP activates phosphokinase A (PKA) which
phosphorylates myosin light chain kinase (MLCK) and renders it
inactive. An inactive MLCK means that the myosin head cannot
be phosphorylated; the myosin is not prepared to bind to actin and
cause contractions, so relaxation occurs. Salbutamol is a specific β2-
adrenoreceptor agonist
Gi - G protein
inhibits adenylate cyclase
Gi inhibits adenylate cyclase. Instead of making cAMP, it slows the production of cAMP, and the cAMP levels go down.
Example - Misoprostol (Cytotec®) causes uterine contractions. It is commonly
used as an abortifacient and for the treatment of postpartum hemorrhage. It can also be used to induce labour at term.
Misoprostol binds to two types of receptors found on the uterus: the EP1 and EP2. There are at least three types of prostaglandin E receptors, designated EP1, EP2, and EP3. The EP3 receptor is coupled to Gi. Gi inhibits adenylate cyclase and thus leaves calcium in the sarcoplasm , and allows the calcium to initiate smooth-muscle contractions.
Gq - G protein
activates phospholipase C (PLC), after which PLC cleave phosphatidyl inositol bisphosphate (PIP2). The cleaved PIP2 yields inositol triphosphate (IP3) and diacylglycerol (DAG), the second messengers. IP3 binds to the sarcoplasmic reticulum and allows calcium release into the cytoplasm. This calcium can trigger smooth-muscle contraction. DAG activates certain targets such as protein kinase C, which will also enhance contractions and open extracellular calcium
channels.
The Gq protein can be activated with different receptors. Drugs such as
ergonovine use α1-receptors whereas misoprostol activates the Gq protein
after binding to the EP1 receptor.
Example - Ergonovine is another drug used to cause contraction of the uterus.
It is very effective in treating postpartum hemorrhage and is often used as abortifacient. It is not used for induction of labour because then contractions are too vigorous and prolonged.
The Gi and Gq mechanisms can complement each other when drugs
that use these mechanisms are combined.
