1.3. Signal transduction: receptors, G proteins, second messengers. Flashcards
- How do cells communicate to each other?
Cells communicate by releasing extracellular signal molecules like hormones and neurotransmitters that bind to receptor proteins located in the plasma membrane, cytoplasm or nucleus.
- What are the 4 types of extracellular signing molecules?
- Peptides and proteins (insulin)
- Amines (epinephrine & norepinephrine)
- Steroid hormones (aldosterone, estrogen)
- Small molecules (a.a., nucleotides, ions, gases)
How are intracellular signals amplified?
- The signal is transduced into the activation or inactivation of intracellular messengers.
- Intracellular signaling proteins (e.g., kinases, phosphatases etc) interact with and regulate the activity of target proteins, thereby modulate the cellular function
- Path:
Signaling molecule
-> Receptor protein
-> Intracellular signaling
-> Target proteins
- What are the 6 basic mechanisms of intercellular (cell-to-cell) communication?
- Contact-dependent
- Paracrine
- Autocrine
- Synaptic
- Endocrine
- Gap junction
- 6 basic mechanisms of intercellular (cell-to-cell) communication
a/ Mechanism of contact-dependent?
signaling molecule of one cell binds directly to a plasma membrane receptor of another cell
- 6 basic mechanisms of intercellular (cell-to-cell) communication
b/ Mechanism of paracrine?
molecules are released and act locally on another type of cell
- 6 basic mechanisms of intercellular (cell-to-cell) communication
c/ Mechanism of autocrine?
release of a molecule affects the same cell or the other cells of the same type:
- 6 basic mechanisms of intercellular (cell-to-cell) communication
d/ Mechanism of Synaptic?
Synaptic: release neurotransmitters at synapse which affects the function of other neurons or cells (fast; millisecond)
- 6 basic mechanisms of intercellular (cell-to-cell) communication
e/ Mechanism of Endocrine?
hormones are secreted into blood, which are widely dispersed in the body (slow; sec to min)
- 6 basic mechanisms of intercellular (cell-to-cell) communication
f/ Mechanism of Gap junction?
Gap junction: junctions that allow intracellular signal molecules to diffuse from the cytoplasm of a cell to an adjacent cell.
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4a. The role of receptors in cell communication
Receptors receive signals from first messengers (e.g., epinepherine or neurotransmitters) and these can lead to a cascade of complexed reactions which results in yield of second messengers like cAMP that affect cellular function.
4b. 5 Requirements of a receptor in cell communication
1/ ‘’bifunctional’’ – they both recognize the ligand and produce a biological response in the target cell
2/ High affinity (recognize ligands in low concentration) (10-9 mM)
3/ Reversible binding to their mediators
4/ Receptor-ligand binding is specific, but not always
5/ Receptor-ligand binding is able to be saturated (reach a point where all receptors already are bound)
- What are first messengers and second messengers?
First messengers are external mediators (insulin,..)
Second messengers
Examples
Ca2+
IP3
DAG
cGMP
Arachidonic acid
- ligands
a/ classification of ligands based on how the receptors bind to ligand
1/ Agonist
- Full agonist: has 100% efficacy -> provokes biological response
- Partial agonist: less than 100% efficacy
2/ Antagonist: has 0% efficacy, but occupies a receptor site (thus, blocks both agonists and inverse agonist)
- Ligands
a/ classification of ligands based on locations
1/ Lipophobic
- Bind to plasma membrane receptors
2/ Lipopholic
- Must depend on carrier proteins
- Bind to plasma membrane receptors
- Bind to intracellular receptors including cytosol and nucleus receptors
- What are the 2 types of intracellular signaling that act as molecular switch?
- Signaling by phosphorylation
- Signaling by GTP-binding protein
- 2 types of intracellular signaling proteins that act as molecular switch
a/ Mechanism and example of Signaling by phosphorylation
1/ Mechanism: ATP phosphorylates signaling proteins, activating them when they have a bound phosphate
2/ For example, glycogen phosphorylase is activated by phosphorylation
- 2 types of intracellular signaling proteins that act as molecular switch
b/ Mechanism of Signaling by GTP-binding proteins
1/ GTP can become bound to the G-proteins (hence their name, G-protein is short for guanine nucleotide binding protein), and binding GTP makes them active
2/ GEF (guanine exchange factor) removes GDP from inactive G-proteins, which allows binding of GTP/reactivation
3/ To deactivate, GAP (GTPase activating protein) stimulates the G-protein’s intrinsic GTPase activity, helping it to cleave the phosphate from its bound GTP, reforming GDP and leaving the G-protein inactive
- Definition of signal transduction
Signal transduction is a Process by which an extracellular (EC) signal is converted to an intracellular signal, which is transmitted through a cell as a series of molecular events, eventually resulting in a cellular response.
- List 4 classes of plasma membrane receptor
1/ G-protein-coupled receptors (GPCRs or 7TM)
2/ Ligand-gated ion channels
3/ Receptors which possess catalytic activity
4/ Receptors associated with an effector with catalytic activity
- Classification of all receptors
1/ G-protein-coupled receptors (GPCRs or 7TM)
- E.G, muscarinic ACh receptor (mAChR)
2/ Ion channel receptors
- E.g, nicotinic ACh receptor (nAChR)
3/ Receptors with enzymatic activity
- Guanylyl cycle (ex: ANP receptor)
- Ser/Thr-kinase (ex: TGFα receptors)
- Tyrosine-kinase (ex: growth factor/insulin receptors)
4/ Enzyme-linked receptors (no intrinsic enzymatic activity)
5/ Regulated intramembrane proteolysis (RIP)
- G-Protein-coupled receptors (GPCRs)
a/ Structure of G-Protein-coupled receptors (GPCRs)
1/ GPCRs have 7 transmembrane domains
2/ GPCRs are heterometric
- They have α (alpha), β (beta) and γ (gamma) subunits
- G-Protein-coupled receptors (GPCRs)
b/ Mechanism of GPCR activation and effector activation
- Agonist ligand binds -> receptor activates
- G proteins interact with receptor leads to…
a/ Receptor conformational change
b/ GDP to GTP exchange
c/ G-protein activated - Activated G-protein (GTP-bound) dissociates from receptor
- α-GTP dissociates from βγ-subunit
- α-GTP and βγ-subunits interact with their appropriate effectors
- α-GTP hydrolyses into GDP -> inactivates α + promotes reassembly of trimer
- G-Protein-coupled receptors (GPCRs)
b/ The role of GPCR
1/ Heterotrimeric G proteins function as transducers to activate many signaling pathways.
2/ One ligand can be bound to distinct receptors
- G-Protein-coupled receptors (GPCRs)
c/ The 5 types of GPCR
1/ Gs proteins (s = stimulatory)
2/ Gi proteins (Inhibitory)
3/ Golf (olfactory)
4/ Gq (G11) proteins
5/ G12/13 proteins
- G-Protein-coupled receptors (GPCRs)
d1/ The role of Gs proteins
Regulates adenylyl cyclase, resulting in increased cAMP
- G-Protein-coupled receptors (GPCRs)
d2/ The examples of Gs proteins
1/ β-adrenergic receptor
2/ ACTH receptor
3/Glucagon receptor
*Note: the pituitary hormone adrenocorticotropin (ACTH)
- G-Protein-coupled receptors (GPCRs)
d3/ The mechanism of Gs proteins
1/ α-GTP increases the activity of adenylyl cyclase (AC)
2/ AC converts ATP to cAMP
3/ cAMP activates protein kinase A (PKA)
4/ phosphodiesterase (PDE) helps break down cAMP
- G-Protein-coupled receptors (GPCRs)
e1/ The mechanism and function of Gi/Go G-protein
Gi/o inhibits AC activity -> decreases the cAMP production
- G-Protein-coupled receptors (GPCRs)
e2/ The 4 functions of Gi/Go G-protein
1/ Inhibition of adenylyl cyclase (cAMP↓)
2/ Activation of K+-channels (leads to hyperpolarization of cells)
3/ Inhibition of Ca2+-channels (can be activated by PKA from Gs)
4/ Phospholipase A2 activation -> arachidonic acid release
- G-Protein-coupled receptors (GPCRs)
e3/ The 3 examples of Gi/Go G-protein
(1) α2-AR (Alpha-2 adrenergic receptor)
(2) M2 + M4 ACh receptor (Muscarinic acetylcholine receptor M4 and M2)
(3) opiate receptors
- G-Protein-coupled receptors (GPCRs)
f/ The mechanism of Golf G-protein
- Odorant molecules will reach the odorant receptor
- G⍺-olf is activated
- Adenylyl cyclase activity increases
- cAMP concentration increases