If the signaling molecule is hydrophilic it cannot cross the plasma membrane but its receptor will be located at the cell surface. Cell-surface receptors are membrane-spanning proteins that protrude into the cell exterior with their signal-binding domains.
The location of cell-surface receptors makes it necessary to transmit the signal from the plasma membrane (the activated receptor) to other parts of the cell. The information from a first messenger (an intercellular signal, here the hormone) is transmitted to a second messenger (an intracellular signal).
In order to understand the concept of second messenger we will discuss it with a specific example:
The action of the hormone epinephrine on muscle cells in mammals.
The hormone's effect on muscle cells is a rise in intracellular glucose concentration providing energy in antissipation of increased mucle activity. This becomes necessary for example when sudden flight seems required.
1. Epinephrine (the first messenger, also called adrenaline) is excreted from specialized cells, carried with the blood stream and eventually arrives at the muscle cells.
2. Here it binds to its specific receptor (Fig. 13.12). The epinephrine receptor belongs to a large family of cell-surface receptors called G protein-coupled receptors. When activated they all transmit their signal via the activation of the small guanosine nucleotide-binding protein called G protein. G protein in its inactive state has bound a GDP. The activated epinephrine receptor exchanges the GDP in the G protein for a GTP. This causes the G protein to undergo transformation into its active state.
3. In muscle cells (Fig. 13.11) the activated G protein in turn will activate an enzyme called adenylyl cyclase which like the epinephrine receptor is also localized in the plasma membrane. The enzyme catalyzes the formation of cyclic AMP (cAMP) from ATP. cAMP is a second messenger that carries the signal from the plasma membrane to the interior of the cell. cAMP also acts as second messenger in many other cells and other intracellular signal transductions.
(Structure of phosphate and ribose in cAMP to show its cyclic nature, Fig. 13.18)
4. The activity of adenylyl cyclase leads to a rise in cAMP concentration. This high cAMP concentration in turn leads to the next step in intracellular signal transduction: the activation of the cAMP-dependent protein kinase or protein kinase A (Fig. 13.19).
5. As the name says, protein kinase A can phosphorylate proteins. It specifically phosphorylates two proteins in muscle cells (Fig. 13.20):
glycogen synthase which becomes inactive and therefore will not use glucose anymore to synthesize glycogen,
and glycogen phosphorylase kinase, another protein kinase which is activated upon phosphorylation.
Active glycogen phosphorylase kinase acts, as its name says, by specifically phosphorylating the enzyme glycogen phosphorylase. This leads to an activation of glycogen phosphorylase which will catalyze the breakdown of glycogen to glucose.
Epinephrine, via protein kinase A, therefore acts two-fold to increase glucose concentrations in the muscle cell: it induces the activation of the enzyme that produces glucose from the storage molecule glycogen (glycogen phosphorylase) and it induces the inhibition of the enzyme that consumes glucose to form glycogen (glycogen synthase).
Phosphorylation of a protein via a protein kinase is a frequent step in intracellular signal transduction. The reaction can even be arranged in whole phosphorylation cascades where one protein kinase phosphorylates another which in turn phosphorylates another and so on.