Endocrine signalling occurs when substances (hormones) are secreted by cells and travel in the bloodstream to distant target cells. In paracrine signalling, cells secrete local chemical mediators that act only on cells in the immediate environment. Paracrine signalling molecules are rapidly internalized, destroyed or immobilized such that their effects can be limited to the local environment. Synaptic signalling occurs when molecules are released vesicles at specialized neuronal cell junctions called synapses. The molecules, neurotransmitters, diffuse across the synaptic cleft and act only on the postsynaptic target cell. Protein receptor molecules on or within the target cells bind to the hormone, paracrine or neurotransmitter and a response is initiated. Often the same molecules are endocrine, paracrine or neurotransmitter, the differences lie in the rapidity and selectivity of the delivered signal.

The receptor mechanisms vary for cellular communication molecules based on their solubility in water. Those, such as neurotransmitters and proteins are water soluble and cannot cross the cell membrane without help. Others such as lipid soluble steroids can cross the lipid bilayer to bind to intracellular receptors. These hydrophobic molecules must be carried in the blood stream bound to transport proteins and therefore their half-life in the bloodstream is hours to days in contrast to hydrophilic molecules which are broken down within seconds. Therefore, water soluble signaling molecules usually mediate responses of short duration, while hydrophobic molecules mediate longer lasting responses.

Intracellular receptors
Small hydrophobic signalling molecules (steroid and thyroid hormones) pass through the target cell membrane to bind to intracellular receptors in the cytoplasm or nucleus. The hormone receptor complex undergoes a conformational change that increases the receptors affinity for DNA and enables it to bind to specific genes in the nucleus and regulate transcription. Binding to specific genes activates or suppresses transcription of those genes. DNA recognition sites associated with steroid-hormone-responsive genes function as receptor dependent transcriptional enhancers. The products of some of these genes may in turn activate other genes to produce a delayed secondary effect.

Cell Surface receptors
All hydrophilic molecules and the hydrophobic prostaglandins effect cellular responses via specific cell membrane receptors on the target cell. These protein receptors bind the signalling molecule with great affinity and transduce the signal into intracellular signals that affect cellular behavior. Cell surface receptors do not regulate gene expression directly. They relay a signal across the cell membrane and the response of the target cell depends on intracellular second messenger molecules such as cAMP, inositol phosphate, or calcium.

There are three families of cell surface receptors based on signal transduction mechanisms.

Channel-linked receptors-- These are transmitter gated ion channels involved in rapid synaptic signalling as in nervous tissue or the neuromuscular junction. A specific transmitter can rapidly open or close ion channels upon binding to its receptor thus changing the ion permeability of the cell membrane. All of these receptors belong to a family of similar multipass transmembrane proteins.

Catalytic receptors-- These receptors behave as enzymes when activated by a specific ligand. Most of these have a cytoplasmic catalytic region that behaves as a tyrosine kinase. Target proteins are phosporylated at specific tyrosine residues thus changing their activation state. The insulin receptor functions in this way.

G-protein linked receptors-- When bound to a specific ligand these receptors indirectly activate or inactivate a separate plasma membrane bound enzyme or ion channel. The interaction between the receptor and the affected enzyme or ion channel is mediated by a GTP binding protein. G-protein linked receptors initiate a cascade of chemical events within the target cell that usually alter the concentration of small intracellular messengers such as cAMP or inositol triphosphate. These intracellular messengers in turn alter the behavior of other intracellular proteins. cAMP levels affect cells by stimulating cyclic AMP-dependent protein kinase to phosphorylate specific target proteins. Calcium levels modify the activity of certain enzymes by binding to the calcium binding protein calmodulin that then activates target proteins. The effects of all these second messengers are rapidly reversible when the extracellular signal is removed. The response of cells to external signals initiates signalling cascades that can greatly amplify and regulate various inputs.