### Cytokine Receptors

#### Structure
1. **General Structure**:
- Composed of an extracellular domain for ligand binding, a single transmembrane helix, and an
intracellular domain for initiating signal transduction.

2. **Types**:
- **Class I cytokine receptors (Hematopoietin receptors)**: Feature conserved motifs like the
WSXWS sequence and are involved in hematopoiesis (e.g., IL-2 receptor).
- **Class II cytokine receptors**: Have conserved cysteine-rich domains and include receptors
for interferons and certain interleukins (e.g., IFN-γ receptor).
- **TNF receptors**: Characterized by cysteine-rich domains and are involved in inflammation
and apoptosis (e.g., TNF receptor).
- **IL-1 receptor family**: Contains an intracellular Toll/IL-1 receptor (TIR) domain, essential for
inflammatory responses (e.g., IL-1 receptor).

#### Function
1. **Ligand Binding**:
- Cytokines bind to their specific receptors, leading to receptor dimerization or oligomerization,
which is crucial for initiating downstream signaling.

2. **Signal Transduction**:
- **JAK-STAT Pathway**: Predominantly used by class I and II cytokine receptors.
- **Steps**:
- Cytokine binding induces receptor dimerization.
- Receptor-associated Janus Kinases (JAKs) phosphorylate each other and the receptor.
- Signal Transducers and Activators of Transcription (STATs) dock at phosphorylated sites,
are phosphorylated by JAKs, dimerize, and translocate to the nucleus to regulate gene
expression.

3. **Biological Functions**:
- Regulation of immune responses.
- Control of hematopoiesis.
- Mediation of inflammation and cell survival mechanisms.

### G Protein-Coupled Receptors (GPCRs)

#### Structure
1. **General Structure**:
- Characterized by seven transmembrane alpha-helices.
- Possess an extracellular N-terminus and an intracellular C-terminus.

2. **Domains**:
- **Extracellular loops**: Important for ligand binding and specificity.
- **Transmembrane helices**: Span the cell membrane, creating a ligand-binding pocket.
- **Intracellular loops**: Interact with G proteins and other signaling molecules.

#### Function
1. **Ligand Binding**:
- Binding of a ligand (e.g., hormone, neurotransmitter) induces a conformational change in the
GPCR, which activates the associated G protein.

2. **Signal Transduction**:
- **G Protein Activation**:
- The conformational change in the GPCR facilitates the exchange of GDP for GTP on the
alpha subunit of the G protein.
- The G protein dissociates into the active alpha subunit and the beta-gamma dimer, both of
which can regulate different effector proteins.

- **Second Messengers**:
- **cAMP Pathway**:
- Activated G_s proteins stimulate adenylate cyclase, increasing cAMP levels, which activate
Protein Kinase A (PKA).
- **Phosphatidylinositol Pathway**:
- G_q proteins activate phospholipase C, producing IP_3 and DAG.
- IP_3 induces calcium release from the ER, while DAG activates Protein Kinase C (PKC).

3. **Biological Functions**:
- GPCRs are involved in various physiological processes, including sensory perception (vision,
taste, smell), mood regulation, immune response, heart rate, and digestion.

### G Protein Cycle and Termination

#### Heterotrimeric G-proteins

1. **Composition**:
 - Consist of three subunits: alpha, beta, and gamma.
- The alpha subunit binds GDP/GTP and has intrinsic GTPase activity.
- The beta and gamma subunits form a stable dimer.

#### G-protein Cycle

1. **Activation**:
- Ligand binding to GPCR activates the receptor.
- Activated GPCR promotes the exchange of GDP for GTP on the alpha subunit.
- GTP-bound alpha subunit dissociates from the beta-gamma dimer.

2. **Effector Activation**:
- Both the alpha-GTP and beta-gamma subunits can interact with and regulate various effector
proteins (e.g., adenylate cyclase, phospholipase C).

3. **Termination**:
- The intrinsic GTPase activity of the alpha subunit hydrolyzes GTP to GDP, terminating the
signal.
- Regulatory proteins such as RGS (Regulator of G protein Signaling) accelerate GTP
hydrolysis.

### Effects of Bacterial Toxins

#### Cholera Toxin

1. **Mechanism**:
- ADP-ribosylates the G_s alpha subunit, locking it in the active GTP-bound state.
- Leads to continuous activation of adenylate cyclase, resulting in elevated cAMP levels.

2. **Outcome**:
- Excessive cAMP causes prolonged activation of PKA, leading to ion and water efflux in the
intestines and severe dehydration (diarrhea).

#### Pertussis Toxin

1. **Mechanism**:
- ADP-ribosylates the G_i alpha subunit, preventing GDP-GTP exchange.
- Inhibits the ability of G_i to inhibit adenylate cyclase.

2. **Outcome**:
- Results in increased cAMP levels, disrupting cellular functions and contributing to the
 - Results in increased cAMP levels, disrupting cellular functions and contributing to the
symptoms of whooping cough.

### Cyclic AMP (cAMP)-Based Signal Transduction

#### Regulation of cAMP Synthesis and Degradation

1. **Synthesis**:
- Adenylate cyclase, activated by G_s proteins, converts ATP to cAMP.

2. **Degradation**:
- Phosphodiesterase (PDE) enzymes degrade cAMP to AMP, ensuring the signal is transient.

#### Intracellular Signaling Mechanisms

1. **cAMP Activation of PKA**:
- cAMP binds to the regulatory subunits of Protein Kinase A (PKA), causing their dissociation.
- The released catalytic subunits of PKA phosphorylate various target proteins, modulating
their activity.

2. **Regulation of Gene Expression**:

- PKA phosphorylates the transcription factor CREB (cAMP Response Element-Binding
protein).
- Phosphorylated CREB binds to cAMP response elements (CRE) in DNA, altering gene
transcription.

### Cyclic GMP (cGMP)-Based Signal Transduction

#### Regulation of cGMP Synthesis and Degradation

1. **Synthesis**:
- Guanylate cyclase, activated by nitric oxide (NO) or natriuretic peptides, converts GTP to
cGMP.

2. **Degradation**:
- PDE enzymes degrade cGMP to GMP, controlling the duration of the signal.

#### Intracellular Signaling Mechanisms

1. **cGMP Activation of PKG**:
- cGMP binds to and activates Protein Kinase G (PKG).
- PKG phosphorylates various target proteins, regulating smooth muscle relaxation, platelet
function, and other processes.
### Calcium-Based Signal Transduction

#### Regulation of Cytosolic Calcium Concentration

1. **Sources of Calcium**:
- **Extracellular Influx**: Voltage-gated calcium channels and receptor-operated channels.
- **Intracellular Release**: IP_3-mediated release from the ER, ryanodine receptor channels.

2. **Removal of Calcium**:
- **Pumps**: SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca^2+-ATPase) and PMCA (Plasma
Membrane Ca^2+-ATPase).
- **Exchangers**: NCX (Na^+/Ca^2+ exchanger).

#### Calcium Activation of Calmodulin-Dependent Kinase (CaMK)

1. **Mechanism**:
- Ca^2+ binds to calmodulin, causing a conformational change.
- Activated calmodulin binds to CaMK, leading to its activation.
- CaMK phosphorylates various target proteins, influencing cellular processes.

#### Calcium Activation of Phosphatases

1. **Calcineurin**:
- A Ca^2+/calmodulin-dependent phosphatase.
- Dephosphorylates NFAT (Nuclear Factor of Activated T-cells), allowing it to translocate to the
nucleus and regulate gene expression.

### Phospholipid-Based Signal Transduction

#### Regulated Phospholipid Metabolism

1. **Phospholipase C (PLC)**:
- Hydrolyzes PIP2 into IP3 and DAG.
- IP3 releases Ca^2+ from the ER, and DAG activates PKC.

2. **Phospholipase D (PLD)**:
- Hydrolyzes phosphatidylcholine to produce phosphatidic acid (PA), a signaling molecule.

#### Diacylglycerol (DAG) and Protein Kinase C (PKC)

1. **Mechanism**:
- DAG, along with Ca^2+, activates PKC.
- PKC phosphorylates various target proteins, affecting cellular responses.
 - PKC phosphorylates various target proteins, affecting cellular responses.

#### PIP3 Kinases and Protein Kinase B (Akt)

1. **Mechanism**:
- PI3K converts PIP2 to PIP3.
- PIP3 recruits Akt to the membrane, where it is phosphorylated and activated.
- Activated Akt phosphorylates target proteins involved in cell survival, growth, and metabolism

#### Phospholipase A2 (PLA2) and Generation of Arachidonic Acid Metabolites

1. **Mechanism**:
- PLA2 cleaves phospholipids to release arachidonic acid.
- Arachidonic acid is converted to eicosanoids (prostaglandins, leukotrienes), which are
involved in inflammation and other responses.

### Integration of Signal Transduction Pathways into Networks

1. **Cross-Talk**:
- Pathways often interact, modulating the intensity, duration, and specificity of the response.
- Examples include crosstalk between cAMP and calcium signaling, as well as integration of
PI3K/Akt and MAPK pathways in cell growth and survival.

2. **Coordination**:
- Ensures that cellular responses are coordinated and appropriate to the physiological context.
- Allows for fine-tuning and adaptability in signal transduction.

These detailed notes should cover all the essential aspects you need for your exam. Good luck!