What is the difference between a first messenger and a second messenger?

First messengers are extracellular signaling molecules such as hormones or neurotransmitters that bind to cell-surface receptors and activate intracellular signaling pathways. Since these molecules cannot physically cross the cell membrane, they rely on second messengers to propagate and amplify the signal within the cell.

Second messengers are non-protein intracellular signaling molecules that relay extracellular signals received at receptors to target molecules within the cytosol. Common second messengers include calcium, cyclic AMP, cyclic GMP, inositol trisphosphate (IP₃) and diacylglycerol (DAG).