The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
5-hydroxytryptamine (5-HT, or serotonin) neurotransmitter receptors. Several others exist but are not well-characterized, or have redundant functions with the four main receptor types. The 5-HT1A receptor is the most abundant in the central nervous system (CNS), and it is the only inhibitory neurotransmitter of the four. The 5-HT2A, 5-HT3, and 5-HT4 receptors are all excitatory. As for histamine, there are four receptors, termed H1, H2, H3, & H4. The H1, H2, and H4 receptors are excitatory. The H3 receptor is inhibitory in that it inhibits release of histamine itself.
Neurotransmitters constitute the first message in brain communication. However, the neurotransmitter message that is conveyed to the specific receptor on the cell membrane needs to continue inside the cell. The process by which this occurs is called ‘signal transduction’, and there are two different ways for signal transduction to be achieved. During the discussion above of the glutamate/aspartate receptors, there was mention of the terms ionotropic and metabotropic. All neurotransmitter receptors share a similar signaling mechanism with either the ionotropic or metabotropic receptors. The ionotropic receptors form ion channels between the extracellular and intracellular fluid, and are permeable to specific ions, such as potassium (K+), chloride (Cl-), and calcium (Ca2+). The metabotropic receptors convey their signal to the brain cell in much more complicated ways, using a variety of small organic molecules, proteins, and sometimes fatty acids. Some receptors are both ion channels and metabolic signalers.
Ion channel neurotransmitter receptors can be either excitatory or inhibitory. K+ channels that are excitatory achieve this by lowering the conductance for potassium across the plasma membrane, and vice versa (inhibitory K+ channels raise its conductance). Excitatory K+ channel receptors include M1, metabotropic subgroup I, 5-HT2A, 5-HT4, a1, b1, and both H1 and H2. Inhibitory K+ channel receptors include M2, D2, GABAB, 5-HT1A, and a2. Ca2+ channels are excitatory if they are postsynaptic (the classical dendritic receptor location), and inhibitory if they are presynaptic (axon). Excitatory Ca2+ channel receptors often allow for other positively charged ions (cations) to enter the channel. Excitatory Ca2+ channel receptors include cholinergic nicotinic, NMDA, AMPA, and 5-HT3. Inhibitory Ca2+ channel receptors are D2, GABAB, metabotropic subgroups II and III, and a2. Cl- channels raise Cl- conductance and are always inhibitory; they include GABAA and glycine. Sodium (Na+) channel receptors are inhibitory and raise Na+ conductance; the receptor in the brain for this is b2.
As can be seen above, there is a significant amount of redundancy in the functions of ion channel receptors. Metabolic receptors are no exception as well. There are two major signal transduction pathways in the brain: the inositol triphosphate/diacylglycerol (IP3/DAG) pathway, and the cyclic adenosine monophosphate (cAMP) pathway. There are several pathways that branch off from these two main pathways, and there is also significant communication, or crosstalk, between the two major pathways. The IP3/DAG pathway is always excitatory. The excitatory receptors that are upstream of IP3 and DAG are M1, metabotropic subgroup I, 5-HT2A, a1, H1, and H4. Functionally, the cAMP pathway is more complicated. It can be either excitatory or inhibitory, and to complicate matters further, raising or lowering cAMP levels can be either excitatory or inhibitory. The excitatory receptors that raise cAMP levels are b1 and H2. Inhibitory receptors that raise cAMP levels are D1 and b2. Inhibitory receptors that lower cAMP levels include M2, D2, metabotropic subgroups II and III, 5-HT1A, and a2.
There are dozens of different small molecules and proteins that are involved in both major signal transduction pathways, and only the main, well-defined molecules and proteins will be mentioned. Structurally, the cAMP pathway is relatively straightforward. The model cAMP pathway is the norepinephrine b1 receptor pathway. Norepinephrine binds to the b1 receptor—although in an inhibitory model it would bind to the b2 receptor (cAMP would still be raised). The b1 receptor then activates a modulatory protein termed ‘Gs’ (Chen, et. al., 1999) for G-stimulatory; the b2 receptor communicates with a ‘Gi’ inhibitory protein. The Gs-protein then activates an enzyme called adenylyl cyclase (Menkes, Rasenick, Wheeler, and Bitensky, 1983). Adenylyl cyclase then produces cAMP, and raises its level inside the cell. Elevated cAMP then activates a very important enzyme, protein kinase A (PKA), which then modifies a variety of other proteins (substrates) (Walaas & Greengard, 1991). PKA modifies downstream proteins by a mechanism known as phosphorylation, where the enzyme transfers a high-energy phosphate group to the downstream (substrate) protein. Importantly, PKA activity