Pharmacology - Drug Targets - Catalytic & Nuclear Receptors Flashcards
structure of catalytic receptors: extracellular domain
Contains a ligand-binding site where peptide or protein ligands bind.
Examples: Hormones or growth factors.
structure of catalytic receptors: transmembrane domain
Anchors the receptor within the cell membrane
structure of catalytic receptors: intracellular domain
Elicits the enzyme activity or associates with enzyme molecules.
This region often includes tyrosine kinase or guanylyl cyclase activity
What happens in the ligand binding and activating of catalytic receptors?
- Binding of a ligand (e.g., peptide or protein) to the extracellular domain
induces dimerisation of the receptors. - Dimerisation activates the enzymatic intracellular domain.
- Activation results in protein phosphorylation and downstream signalling cascades
What is the clinical relevance of catalytic receptors?
Catalytic receptors are critical targets in drug development for diseases such as cancer, diabetes, and cardiovascular conditions. Their dysfunction or overactivation
often leads to pathological conditions, making them key therapeutic targets.
What are RTKs? (receptor tyrosine kinases)
- RTKs are a family of membrane-bound receptors that are activated by
binding to specific growth factors, hormones, and cytokines. - They contain intrinsic tyrosine kinase activity in their intracellular domain
What are the functions of RTKs?
- Cell proliferation: Division of cells.
- Differentiation: Specialization of cells.
- Survival: Prevention of programmed cell death (apoptosis).
- Metabolism: Regulation of energy and nutrient usage.
What is the clinical relevance of RTKs?
- Hyperactivation:
- Overactivation of RTKs can result in uncontrolled cell growth,
leading to polyp formation, tumours, and cancer. - Therapeutic Target:
- Many cancer treatments (e.g., tyrosine kinase inhibitors) target
RTKs to block their overactivation in malignancies
RTKs: growth factor binding, explain
- A growth factor binds to the extracellular domain of the RTK.
- This interaction triggers dimerisation of two RTK molecules.
RTKs: autophosphorylation?
- Dimerization brings the intracellular tyrosine kinase domains close to
each other. - Each kinase domain autophosphorylates tyrosine residues on its partner
RTK, enhancing their activity
RTKS: signal transduction?
- Phosphorylated tyrosines on the RTK serve as docking sites for signalling
proteins. - Proteins recruited to RTKs typically contain SH2 domains (Src Homology
2), which recognise specific phosphotyrosines. - Recruitment of these signalling proteins enables downstream signalling
pathways to mediate diverse cellular responses.
RTK: cellular responses?
- Multiple signals are generated from a single RTK activation:
- Signal 1: Could lead to proliferation (e.g., cell division).
- Signal 2: Could lead to survival (e.g., anti-apoptotic signals)
What aspect of RTKS control their specificity?
dictated by their SH2 domains
what is the issue with RTK drugs?
*very limited options
* many neurotrophin analogues couldn’t pass through clinical trials (failures)
What is the clinical relevance of ANP and Guanylyl cyclase signalling?
*ANP and Heart Function: ANP is an important biomarker and therapeutic target in heart failure and hypertension due to its vasodilatory and diuretic effects.
*Guanylyl Cyclase Signalling: Pharmacological agents targeting cGMP pathways (e.g.,
phosphodiesterase inhibitors) enhance the effects of ANP, offering therapeutic benefits in cardiovascular diseases
Guanylyl cyclase receptors – cytoplasmic-Nitric oxide what happens?
- endothelial cells release nitric oxide
- Vascular Smooth muscle:
1. NO stimulates cytoplasmic guanylyl cyclase
2. Elevation of intracellular [cGMP]
3. Activation of protein kinase G
4. Smooth muscle relaxation
5. PDE isoform breaks down cGMP
What is the clinical relevance of nitric oxide drugs?
*Cardiovascular Health: NO-mediated pathways are critical for managing
hypertension, angina, and heart failure.
*Pharmacological Advances: Drugs targeting the NO-cGMP pathway (e.g., nitrates, PDE inhibitors) have broad therapeutic applications in vascular and respiratory diseases
cytoplasmic and nuclear receptors: intracellular receptors, location, activation and function?
*Location: Found in the cytoplasm or nucleus of cells.
*Activated by small, lipophilic ligands such as steroids, thyroid hormones, and other hydrophobic molecules.
*Function as transcription factors, regulating gene expression
mechanism of action of intracellular receptors/ transcription factors of cytoplasmic and nuclear receptors?
*Ligands (e.g., steroid hormones) diffuse across the plasma membrane due to
their lipophilic nature.
*Bind to cytosolic receptors (if the receptor is cytoplasmic) or directly to
nuclear receptors.
*Ligand-receptor complex translocates to the nucleus (if required), binds to
specific DNA sequences (hormone response elements), and modulates
transcription of target genes.
*Leads to synthesis of specific proteins that produce diverse biological effects.
What is the clinical relevance of the intracellular receptors or cytoplasmic and nuclear receptors?
*Therapeutic Target: Nuclear receptors are prominent drug targets due to their direct involvement in transcriptional regulation.
*Diseases:
* Hormone-sensitive cancers (e.g., breast and prostate cancer).
* Metabolic disorders (e.g., diabetes via PPARs)
What are the different drug targets and their response times?
*ligand gated ion channels = fastest response (milliseconds to seconds)
*voltage gated ion channels = rapid response (milliseconds)
*G-protein coupled receptors =
moderate response time (seconds to minutes)
*enzymes = lower response (minutes to hours)
* transporters = response varies (minutes to hours)
* catalytic receptors = response in minutes
* nuclear receptors = slowest
(hours to days)
