| Schematic illustration of
major second messenger pathways in the brain. Gs and Gi/o, respectively,
mediate the ability of neurotransmitter receptors (R) to activate or inhibit
adenylyl cyclase, the enzyme that catalyzes the synthesis of cAMP. Also
shown in the figure is the ability of G-protein bg subunits, released potentially
by any type of G-protein, or Ca2+/calmodulin to stimulate or inhibit different
forms of adenylyl cyclase. Gq and perhaps Gi/o mediate the ability of neurotransmitter
receptors to regulate phospholipase C (PLC), which metabolizes phosphatidylinositol
(PI) into the second messengers inositol triphosphate (IP3) and diacylglycerol
(DAG). IP3 then acts on specific IP3 receptors (IP3R) to increase intracellular
levels of free Ca2+ (also a second messenger in brain) by releasing Ca2+
from internal stores. Increased levels of intracellular Ca2+ also result
from the flux of Ca2+ across the plasma membrane through Ca2+ and other
ion channels, a flux stimulated by nerve impulses and certain neurotransmitters.
As discussed in the text, G-proteins mediate many of the actions of neurotransmitters
on such channels. Increased levels of Ca2+ activate nitric oxide synthase
(NOS), leading to increased levels of nitric oxide and the activation of
cytoplasmic guanylyl cyclase (the enzyme that catalyzes the synthesis of
cGMP) and of ADP-ribosyltransferases (not shown). Other forms of guanylyl
cyclase reside in specific plasma membrane receptors.
These second messengers, in turn, activate specific types of protein kinases. Brain contains one major type of cAMP-dependent protein kinase and of cGMP-dependent protein kinase, although subtypes of these enzymes are differentially expressed throughout the brain. These enzymes phosphorylate a specific array of substrate proteins, which can be considered third messengers. cAMP-dependent protein kinase has a broad substrate specificity, that is, it phosphorylates many substrate proteins and mediates most of the numerous second messenger actions of cAMP in the nervous system. The substrate specificity of cGMP-dependent protein kinase appears to be less broad, although by analogy with the cAMP system it is likely that it mediates many of the second messenger functions of cGMP. Brain contains two major classes of Ca2+-dependent protein kinase. One is activated by Ca2+ and calmodulin and is referred to as Ca2+/calmodulin-dependent protein kinase. Brain contains at least six distinct types of this enzyme: 1-4) Ca2+/calmodulin-dependent protein kinases I, II (several subtypes of this enzyme are known), III, and IV; 5) phosphorylase kinase; and 6) myosin light chain kinase. The other major class is activated by Ca2+ in conjunction with DAG and various phospholipids and is referred to as Ca2+/DAG-dependent protein kinase or protein kinase C; there are at least 7 closely-related variants of this enzyme present in the brain. Protein kinase C and Ca2+/calmodulin-dependent protein kinases II and perhaps I and IV have broad substrate specificities (as indicated by the multiple arrows in the figure) and each probably mediates many of the numerous second messenger actions of Ca2+ in the nervous system. [The figure also illustrates that some of the second messenger actions of Ca2+ in brain are mediated through proteins other than protein kinases.] Not shown in the Figure is the fact that some protein phosphatases are also subject to regulation by second messengers. For example, protein phosphatase 2B, or calcineurin, is activated upon binding Ca2+/calmodulin. Phosphorylation of substrate proteins by these various second messenger-dependent protein kinases alters their physiological activity in such a way as to lead to the biological responses of the extracellular messengers either directly or indirectly through intervening fourth, fifth, sixth, etc. messengers. Modified from Hyman and Nestler, 1993.