Messengers and Receptors

Learning Objectives

• Identify what are first messengers are and their properties

Describe how first messengers interact with receptors

• Identify the key properties of a receptor-messenger interaction

What is cell signalling?

To respond to changes in their immediate environment cells must be able to:

• Receive signals from outside

• Process signals

• Integrate many signals arriving simultaneously

• Communicate - transmit signals near and far

Generally

• A ligand will come in contact with a receptor on the cell surface

• Upon binding it induces another protein called a transducer

• The transducer engages with the receptor and exerts an affect on the effector protein

• The effector protein is responsible for generating a second messenger which can have downstream effects on the cell

First messengers and organismal responses

Examples of different types of first messengers in the body

• These will engage with the cell and induce different biological effects

• Cells can then also transmit new first messengers for other cells as part of a feedback mechansim

Signal Transduction Cascade Example: involving cyclic AMP 7

• Adrenaline is the first messenger which binds to the adrenergic receptor, activating adenylyl cyclase by the G-protein complex

  • The transducer is the G-protein complex

  • The effector is the adenylyl cyclase

  • It produces the second messenger, cAMP

• The signal transduction cascade begins when adenylyl cyclase, a membrane- bound enzyme, is activated by G-protein molecules associated with the adrenergic receptor.

• Adenylyl cyclase creates multiple cyclic AMP molecules, which fan out and activate protein kinases (PKA, in this example).

• Protein kinases can enter the nucleus and affect transcription.

First Messengers

Can be diverse molecules:

• gases (eg, nitric oxide, NO)

• single amino acids (eg, glutamate)

• nucleotides (eg, ATP) 8

• Lipids (eg, prostaglandin)

• Proteins (eg, insulin)

Four Modes of Communication by First Messengers

1. endocrine: messenger (hormones) is produced by specialised tissues, glands

2. paracrine (including autocrine): produced by ordinary tissue (not glands) (such as inflammation)

3. juxtacrine: messenger is attached to the cell for other cells to then come and interact with, cell-cell adhesion (adaptive immune system is an example)

4. synaptic: messenger diffuses within the synaptic cleft

Note: not all first messengers fit neatly into a category, and some may fall into two categories

Function of First Messengers

First messengers can be multi-functional

• As a general rule first messengers do not cross the membrane and act at a receptor at the cell surface

  • Note that hydrophobic first messengers can be transported into cell before reaching the receptor inside the cell, eg the steroid hormones.

First Messengers Need Context to Transmit Signals

The first messenger itself carries no intrinsic message

• The response to the signal requires:

  • The presence of a receptor

  • the cellular context – different cells may decode the information differently

    • E.g. one type of cell replies to the same first messenger by undergoing migration, whereas another with secretion

• Cells that lack the appropriate receptor (or have an inactive receptor) do not respond (non-receiver)

Receptors

Receptors are generally on the cell surface, but can also be inside cells (such as on the nuclear membrane)

• There are 1000s of receptors

• Collectively engage with first messengers to propagate the decoding of that information in signal transduction

• Signal transduction describes the process by which first messengers activate cellular responses (information is decoded for a biological response)

  • Usually involves the simultaneous responses of multiple first messengers

First Messengers are Ligands to the Receptor

Ligands bind reversibly through non-covalent bonds

• Binding thus forms an equilibrium

• (Kd) describes how effective ligands are at binding to a receptor

  • Low Kd = high affinity, strong binding (steep binding curve)

  • High Kd = low affinity, weak binding (binding curve more elongated)

Modulating Signalling

Receptors can bind to different ligands to modulate signalling

Ligands can bind to exert different effects:

• Agonists – stabilise the active state, by binding and lowering the free energy of the active state (green)

  • In this example, the active state is further stabilised by binding to the G protein complex effector protein.

  • Stabilises the state that favours signalling

• Inverse agonists – stabilise the inactive state, by binding and lowering the free energy of the inactive state (red)

• Antagonists – prevent signalling by blocking access for agonists/inverse agonists to bind. They do not otherwise stabilise the active or inactive states (purple)

  • Compete for the same binding site

Sensitivity to First Messengers

Sensitivity to first messengers is affected by abundance of receptors on the cell surface

• The number of occupied receptors at equilibrium is proportional to the total number of receptors on the cell surface.

• The number of occupied receptors needed for a maximal cellular response is only a small fraction of the total number of receptors present on the cell.

  • More receptors on a cell makes them more sensitive to responding to first messengers

• The maximum number of receptors can be measured by progressively increasing ligand until saturation is achieved (see below)

Example: Odor receptors – detecting odorants as first messengers: dogs versus humans

Odor receptors – detecting odorants as first messengers

A dog can detect 10,000–100,000 times less odor concentration than a human

• In a dog, olfactory receptor cells have hundreds of cilia In a human, olfactory receptor cells have 25 cilia

Other properties of ligand binding to receptors

Full response does not require full occupancy of a cell’s receptors.

• EC50 of a pathway depends on what part of the pathway you are looking at (see graph below)