first messengers (ligands) and their

interaction with receptors

I

A selectionof

firstmessengers

A selectionof

firstmessengers

Interaction ligand-receptorwell known

Ligand/receptor interactions vary greatly between small ligands, like neurotransmittors and certain

hormones, and protein ligands, like the cytokines or growth factors

Quantitative aspects of ligand/receptor interactions are well studied for small ligands, binding to ions channels or 7-TM

proteins

Interaction ligand-receptorwell known

Small ligands have a limited number of interactions with their receptor; three in the case of adrenaline (serine, serine and

aspartate)

2

1

3 2

topview

Large protein ligands have a large number of interactions with their receptor (numerous amino acides involved as indicated by

the green surfaces)

Interleukin-1Interleukin-?

Another example of multiple sites of interaction between ligand and receptor, this time in the case of TGF

binding to the EGF receptor

Characteristics of receptor binding: saturable (specific) binding sites

Linear scale Logarithmic scale

Maximum specific binding

EC50

High receptor numbers increase the sensitivity of the system. Cells often express receptors in excess

Characteristics of receptor binding: inhibition of cellular response by an antagonist

Dose responsein presence of antagonist(the presence of the antagonist preventsbinding of adrenaline)

Agonistonly

Antagonists are substances that bind to the receptor without causing a cellular response; in doing so they compete with the action of the physiological ligand.

Agonist are substances that bind to the receptor and mimic the action of the physiological ligand.

Agonists and antagonists are frequently used in pharmacological intervention of disease, for instance -adrenaline antagonists (« -blockers ») are applied to reduce the heart rate and to reduce the force of contraction (in case of a history of cardiac failure)

Relationship between cellular reponse (3), second messenger generation (2) and ligand binding (1)

(1)(2)(3)

Characteristics of receptor binding: a dynamic receptor-ligand interaction

Ligand receptor binding strategy for nerve signal transmission: low affinity acetylcholine receptors (KD 20-80 M) in a very small

volume (the synaptic cleft) with the presence of acetylcholinesterase. This warrants a rapid and, importantly,

transient response.

Rapid and transient receptor occupation, as in the case of acetylcholine at the neuromuscular junction, permits rapid and

transient muscle contraction.

Ligand receptor binding strategy for growth factor signal transduction: very high affinity receptors (KD 100 nM),

slow and long lasting responses. This allows for economization of growth factor production (large proteins

that are diluted in total body volume)..