Pharmacology Part 2 Flashcards
Define receptors
Sensing elements in the complex system of chemical communication within the body
What are receptors the targets of?
- neurotransmitters
- hormones
- mediators (peptide growth factors, chemokines, cytokines)
- therapeutic agents
What does a receptor response to?
By virtue of its ligand selectivity responds to one or more of the signalling molecules
Describe the classification of receptors by basis of structure and function?
- Ligand-gated ion channels (LGICs)- aka inotropic
- G-protein coupled receptors (GPCR) aka metabotropic
- Kinase-linked
- Nuclear
Where are type 1 receptors located and what are they targeted by?
Plasma membrane, targeted by hydrophilic signalling molecules (e.g. fast neurotransmitters)
Where are type 2 receptors located and what are they targeted by?
Plasma membrane, targeted by hydrophilic signalling molecules (e.g. slow neurotransmitters, amino acid-derived and peptide hormones)
Where are type 2 receptors located and what are they targeted by?
Plasma membrane, targeted mail by hydrophilic protein mediators (e.g. insulin, numerous growth factors)
Where are type 4 receptors located and what are they targeted by?
Nuclear receptors (located in the cytoplasm and translocate to the nucleus following activation), targeted mainly by hydrophilic protein mediators (e.g. steroid hormones)
What are ion channels formed from?
Glycoproteins that span the membrane to create an ion conducting pathway
What are ion channels regulated by?
Signals that cause the channel to cycle between a closed state and open state- known as gating
What do open ion channels do?
Conduct selected ions passively town their electrochemical gradient
What may an ion channel be gated by?
- chemical signals (LGICs)
- transmembrane voltage (voltage gated ion channels)
- physical stimuli (including thermal and mechanical injury)
What are LGICs regarded as?
True receptors because they respond to a chemical sign
What are the three main categories of LGICs?
Trimeric
Tetrameric
Pentameric
What do ion channels allow?
Rapid changes in the permeability of the membrane to certain ions
Rapidly altering membrane potential
What are the three states ion channels exist in?
Unoccupied and closed
Occupied and closed
Occupied and open
How do most cell surface receptors signal via second messenger systems?
- many are linked to a cell-membrane-located effectors by intermediary G proteins
- enzyme effectors often synthesise second messenger molecules that, in turn, affect the activity of targets within the cytoplasm
Describe the structure of a G protein receptor?
- Integral membrane protein
- Single polypeptide with extracellular NH2 and intracellular COOH termini
- contains 7 transmembrane spans joined by 3 extracellular and three intracellular loops
- can function as dimers
Describe the structure of a G-protein?
- peripheral membrane protein
- consists of 3 polypeptide subunits (a, b, y)
- contains a guanine nucleotide binding site in the a subunit that can hold GTP or GDP
- exist as multiple types (Gs, Gi, Gq)
What are g-proteins names by?
Their a subunit
How are G-proteins activated?
By agonist binding to the GPCR to which they preferentially couple
What does the inactive state of G-protein require?
The binding of GDP
What localises the a and y subunits in the plasma membrane?
Covalently attached lipid molecules
What does the a subunit contain?
A GTPase domain with Ras and AH subdomains
What is Ras?
The GTPase subunit
What is AH
The aplhahelical subunit which clamps the nucleotide in place
What happens when an agonist binds to a GPCR?
It undergoes a conformational change;
- releases GDP and allows GTP to bind
- separated the receptor from By subunit
- generated a free GTP-bound a-subunit and By dimer (signalling units)
What happens if the agonist dissociated from the receptor?
Signalling can persist
How is the signal terminated?
The a subunit acts as an enzyme to hydrolyse GTP to GDP, terminating the signal
Which receptor is coupled to B-adrenoreceptors?
Gs
Which receptor is couples to M2 muscarinic acetylcholine receptors?
Gi
How do Gs and Gi proteins cause cellular effects?
Via adenylyl cycle converting ATP to cAMP which is in turn used to activate PKA, phosphorylating Ser/Thr residues in target proteins and causing cellular effects
How does the Gq receptor cause cellular effects?
By stimulating Phospholipase C, converting PIP2 to IP2, stimulating the IP3 receptor in the endoplasmic reticulum, allowing influx of calcium and cellular effects/ It also produced DAG as a byproduct of PIP2 to Ip3 which activated protein kinase C
Describe the signalling via insulin?
Binding of insulin causes autophosphorylation of intracellular tyrosine residues
Recruitment of multiple adapter proteins, notably IRS1, that are also tyrosine phosphorylated and eventually cause cellular effects
What are nuclear receptors?
Ligand-gated transcription factors
Describe signalling via Class 1 nuclear receptors
- Steroid hormones enter cells by diffusion across the plasma membrane
- Steroid hormones combine with intracellular receptor
- Combination produced dissociation of inhibitory HSP
- Receptor steroid complex moves to nucleus and forms a dimer, binds to hormone response elements in DNA
- Transcription of specific genes is either transactivated or transpressed to alter mRNA levels
- This transcription can alter the rate of synths of mediator proteins
