Water-Soluble Messenger Pathways (Episode 4)
The water-soluble messengers interact with receptors located on a cell’s plasma membrane. The fact that the receptors interacting with water-soluble messengers are on the plasma membrane is non-trivial. The location of a receptor is crucial to determining what kind of messenger attaches to it. Think about what water-soluble actually means. What it means is that the messenger is hydrophilic or “water-loving.” So water-soluble messengers can’t readily diffuse through the phospholipid bilayer, which has nonpolar, hydrophobic tails. If you recall, the molecules that can readily diffuse through the plasma membrane are nonpolar molecules. Lipid-soluble molecules enter the cell, so they often bind receptors called nuclear receptors. Nuclear receptors are unique intracellular receptors in the cytoplasm or, more commonly, the nucleus. These receptors are structurally very different from plasma membrane receptors that water-soluble messengers bind to, but they still are proteins and have binding and regulatory sites. A water-soluble messenger, because it is hydrophilic or “water-loving” will not bind to receptors inside the cell. This doesn’t mean the plasma membrane receptor only resides on the extracellular membrane. The receptor is an integral protein, so it crosses the lipid bilayer and functions inside the cell. It has a regulatory site in the cell to transmit the message. But, as I said, plasma membrane receptors accept messengers on the extracellular side of the membrane.
Now, this binding leads to a sequence of events that trigger the cell’s response. This sequence of events due to a response is known as signal transduction. Signal refers to receptor binding, and transduction refers to the sequence of events leading to the response. For water-soluble messenger pathways, the binding occurs out of the cell, but the events occur within the cell. The first messenger, the messenger that binds outside the cell, causes the second messengers in the cell to relay information. Something else to note the importance of in the cell is protein kinases, which are enzymes that phosphorylate other proteins. They alter a protein’s structure, and therefore, its function. Change in function can mean the activation or inhibition of the protein. An inactive kinase can be activated by an active kinase. The activation of one kinase to the next can ultimately lead to the cell’s response.
A water-soluble messenger can create a cell response in a few different ways. First, receptors can be ligand-gated ion channels. The ligand, in this case the water-soluble messenger, the primary messenger, binds to the receptor, an ion channel. This binding causes the channel to open and allows for increased ion diffusion. Receptors can also function as enzymes, and most likely, the receptors are receptor tyrosine kinases. Binding of a primary messenger causes conformational change in the receptor so that the enzymatic portion of the receptor, located on the cytoplasmic side, is activated. This phosphorylation can allow proteins to bind and also phosphorylate other proteins. Receptors, instead of being enzymes themselves, can also interact with cytoplasmic Janus Kinases. This is the third type of receptor for this water-soluble messenger pathway. Janus Kinases or JAKS function as a unit with the receptor, and the binding of a messenger causes a conformational change in the receptor, which leads to the activation of the Janus Kinase. The last type is the G-Protein Coupled Receptors. G proteins are a family of proteins often bound to the receptor. They have three subunits: alpha, beta, and gamma. The alpha subunit can bind to GTP and GDP. When the receptor is activated, GTP binds to the alpha subunit, which causes it to separate from the beta and gamma subunits and link up with an enzyme of ion channel near it in the plasma membrane. This binding with the GTP-bound alpha subunit and the plasma membrane protein leads to this protein switching on and eventually leading to a cell response through signal transduction.
