Tema 6 Flashcards
signal transduction path
first messenger (interaction with)
receptor (activation of)
second messenger (activation of)
biochemical processes (activation of)
celular response
FAST VS SLOW PATH
FAST - mins to seconds
the extracellular molecule binds to the membrane receptor
there is an altered protein FUNCTION
it leads to an altered cytosol function
altered cell behaviour
SLOW - mins to hours
the extracellular molecule binds to the membrane receptor
there is an altered protein SYNTHEISS
it leads to an altered cytosol function
altered cell behaviour
COMPLEXITY of information exchange
- Signal reception
- Primary transduction through sequential reactions
- Signal transduction inside the cell
- Signal amplification
- Spreading of the signal
- Modulation by other factors
INTRACELLULAR RECEPTORS
They are specific proteins of the cytosol or nucleus.
they cross the membrane, bind to receptors, and form a complex that will interact with the NUCLEAR DNA in order to MODIFY GENE EXPRESSION
Therefore, they act as REGULATORY TRANSCRIPTION FACTOR
They have a slow biological action
They are called orphan receptors
There are 2 families: classs I (steroid hormones) and class II (thyroid hormones)
intracellular receptor structure
Ligand binding domain
-contains the transcription activation region called AF-2.
DNA binding Domain,
-With two handles of amino acids (Zinc fingers) that attach to the HRE region of DNA (hormone response element).
N-terminal domain
-Highly variable, it contains the region AF-1.
intracellular receptors - class I
Steroid hormone receptors.
Found as monomers in the cytosol or in the nucleus
They are associated with hsp proteins (heat shock proteins).
The hsp separates from the receptor when the ligand binds to the receptor
2 receptor- bound complexes join to form a dimer that binds to DNA with high affinity –> activating (or inhibiting) transcription.
intracellular receptors - class II
Thyroid hormone receptors, retinoid acid, vitamin D, prostaglandins…
Instead of hsp proteins, they are bound to the HRE in the DNA, where they remain
silenced by repressor proteins.
When the ligand binds the receptor, the repressor dissociates and this stimulates transcription.
MEMBRANE RECEPTORS
Structure: extracellular domain, transmembrane domain + cytosolic domain
The activation of membrane receptors generates second messengers
Second messengers are molecules that transfer the information to the effectors through transduction systems
Types of membrane receptors: Ionic channels, enzyme-coupled, coupled to G-proteins
advantages of second messengers
- Amplification of the signal inside the cell
- Larger distribution and divergence in the amount of cellular targets
- Capacity to regulate the signals
types of membrane receptors
ionic channels
enzyme-linked
associated to a G-protein
membrane receptor - bound to ionic channel
The binding of the ligand (first signalling molecule) promotes the opening (or closing) of an ionic channel
Which modifies membrane potential
• Nicotinic colinergic receptor
• GABA receptor
membrane receptor - enzyme coupled
Binding of the ligand to the receptors activates diferent intracellular signalling proteins:
• Tyrosin kinases (MOST FREQUENT)
• Serin-Threonin kinases/phosphatases
• Histidine kinases
• Guanilil cyclase
A signalling cascade of intracytosolic phosphorylations and dephosphorylations is initiated
These proteins behave as second messengers and, besides, they can initiate signalling chains
*if the kinase is part of the receptor itself –> intrinsic (ex. insulin receptor)
*if the tyrosine kinase is not part of the receptor, it is provided by kinases associated to the receptor (prolactin receptor)
membrane receptor- coupled to G protein
The most abundant type of membrane receptors // more than 1000
The most studied:
a. Gs: activates adenylate cyclase
b. Gi: inhibits adenylate cyclase
c. Gq: activates phospholipase C
Very long transmembrane segment, it crosses the membrane up to 7 times
They act as transducers, between receptors and the enzymes which syntethize the second messengers
-Bound to GDP when not active
-Binding of the ligand to the receptor changes their conformation –> replaced by GTP
-Once active, it slides through the inner membrane side in order to exert its action on efector proteins
They use cAMP, cGMP or phospholipids/Ca2+as second messengers.
TRANSDUCTION SYSTEMS AND THEIR SECOND MESSENGERS
Transduction systems –> Second messengers:
Ionic channels –> Na+, Ca 2+
Adenylate cyclase –> cAMP
Guanylate cyclase –> cGMP
Phospholipase C –> DAG, IP3, Ca2+
cAMP
Produced by adenylate cyclase from ATP
cAMP acts as a second messenger:
– Activating protein kinases A (PKA) which phosphorylates diverse proteins
– Modifying protein synthesis of specific transcription factors (CREB, cyclic AMP response element binding protein)
Examples: Catecholamine receptors
*cAMP binds PKA, producing the dissociation of its subunits
*Then, PKA is able to phosphorylate effector proteins (using ATP)
*The phosphorylation of effector proteins can increase or inhibit their activity, producing the cellular response
