Second Messengers: These are intracellular signaling molecules that mediate cellular response to a hormone, drug or neurotransmitter bound to a receptor. The hormone, drug or neurotransmitter is considered to be the initial, or first messenger. When a ligand binds to a receptor, the receptor reacts in a way that transmits the information into the cell. For some receptors, such as the ligand gated ion channel, the receptor itself changes configuration to allow the flow of ions that alter cellular behavior. In other receptors, such as the G-protein coupled receptors, the activation of the receptor by an agonist promotes the recruitment of intracellular events coupled to the receptor. The events that are coupled to the receptor are secondary to receptor-occupancy and serve to carry the signal into the cell. The molecules produced are therefore called the second messenger. Much of our understanding of second messengers is due to the work of Earl W. Sutherland, Jr. in the 1950's. Sutherland demonstrated that the action of epinephrine on the breakdown of glycogen was due to formation of an intermediate. This intermediate was the classic second messenger cAMP. Other second messengers include: cGMP, calcium, IP₃, DAG and NO.