What is a receptor?
Sensing element in the complex system of chemical communication within the body
What are receptors the target of?
Neurotransmitters
Hormones
Mediators such as growth factors, chemokines, cytokines
Therapeutic agents such as agonists, antagonists
What is a autocrine response?
When the signalling molecule targets the signalling cell it was made in
What is a paracrine response?
When the signalling molecule targets a neighboring cell called a target cell
What is an endocrine response?
When the signalling molecule enters the circulation targeting cells all over the body
What are the 4 types of receptor?
Ligand-gated ion channels
G-protein-coupled receptors
Kinase-linked
Nuclear
Where are ligand gated ion channels located?
Plasma membrane and are therefore targets of hydrophilic signalling molecules e.g. neurotransmitters
Where are G-protein-coupled receptors located?
Plasma membrane and therefore targeted by hydrophilic signalling molecules
Where are kinase-linked receptors found?
Plasma membrane and so are targets of hydrophilic protein mediators such as insulin
Where are nuclear receptors found?
In the nucleus and so are targeted mostly by hydrophobic signalling molecules such as steroid and thyroid hormones
What are ion channels made from?
Transmembrane pores that are formed by glycoproteins that span the membrane to form an ion conducting pathway
How are ion channels regulated?
By signals that cause the channel to cycle reversibly between a closed state and an open state known as gating
How do open channels conduct ions?
The ions are passed passively down their electrochemical gradient at rapid rates
What are examples of gates on ion channels?
Chemical signals e.g. ligand gated
Transmembrane voltage e.g. voltage gated
Physical stimuli e.g. thermal and mechanical energy
What are the three types of ligand gated ion channels?
Trimeric
Tetrameric
Pentameric
What is the function of ligand gated ion channels?
Consists of separate glycoprotein subunits that form a central ion conducting channel. Allows rapid changes in the permeability of the membrane to certain ions
What is signalling via second messenger system?
The receptor activation modulates the activity of an effector that is generally an enzyme or ion channel
What are many receptors linked to?
A cell membrane located effector by intermediary G proteins. The enzyme effector usually synthesizes second messenger molecules that will affect the activity of targets within the cytoplasm
What is the pathway of signalling via second messengers?
Signal binds to receptor
This activates a G protein
Which in turn activates an effector enzyme or ion channel
What is the basic structure of a G protein coupled receptor?
It is an integral membrane protein that is made up of a single polypeptide with extracellular NH2 and COOH terminals. It has 7 transmembrane spans that are joined together by 3 extracellular and 3 intracellular connecting loops. Many GRPRs function as dimers i.e. 2 receptors together
What is the basic structure of a G protein?
Is a guanine nucleotide binding protein. It is a peripheral memrane that consists of 3 polypeptide subunits - alpha, beta and gamma
The alpha subunit has a guanine nucleotide binding site that can hold onto GTP/GDP
How is a G protein activated?
Agonist binding to the GPCR to which they preferentially coupled
What is the structure of a g protein when it is inactive?
The guanine nucleotide binding site of the alpha subunit is occupied by GDP
How does the G protein stay attached to the plasma membrane?
Covalent bonds on the alpha and gamma subunits
What does the alpha subunit contain?
A GTPase domain with Ras and AH sub-domains. Ras is the GTPase component whereas AH clamps the nucleotide in place
What happens when the agonist binds to the GPCR?
The alpha subunit releases GDP to allow GTP to bind. This causes the G protein to seperate from the receptor and the beta/gamma dimer. This then results in an alpha unit and a beta/gamma diner
What happens to the G-protein coupled receptor when there is no signalling present?
The receptor is unoccupied
G-protein alpha subunit is bound to GDP
Effector is not modulated
What happens to the GPCR when it is activated?
Agonist binds and the G protein will bind to the receptor. GDP will dissociate from alpha subunit and GTP will bind. G protein dissociated into separate alpha and beta/gamma subunits
How is the signal turned off?
The alpha subunit acts as an enzyme (GTPase) to hydrolyse GTP to GDP and Pi. The G-protein alpha subunit will then recombine with the beta/gamma subunit
How does signalling via nuclear receptors work?
Steroid hormones can enter the cell and will combine with an intracellular receptor causing a conformational change that leads to receptor to move to the nucleus and form a dimer to bind to hormone response elements in DNA. The genes will then be switched off or on to alter mRNA levels and the rate of synthesis of mediator proteins