The Role of Histamine in Mental Illness and Its Attenuation With Vitamin C – Part II
is reduced in depression (Shelton, Mainer, & Sulser, 1996).
One of the substrate proteins that PKA phosphorylates is the aptly termed cAMP response element binding protein (CREB); this is achieved after PKA translocates into the cell’s nucleus (Hagiwara, et. al., 1993). In this cAMP pathway model, CREB then binds to a specific DNA sequence upstream of a gene called brain-derived neurotrophic factor (BDNF), and increases expression of BDNF mRNA (Zafra et al., 1992). The central dogma of molecular biology states that DNA is transcribed into messenger RNA (mRNA), which is then translated (expressed) into protein (Lewin, 1994). In other words, CREB binds upstream of the BDNF gene, signaling an enzyme complex to transcribe the BDNF DNA into mRNA, and that mRNA is then translated into the mature BDNF protein.
BDNF then initiates several positive functions, including supporting the survival and maturation (differentiation) of brain neurons (Hyman et al., 1994), especially serotonin (5-HT) neurons (Mamounas, Blue, Siuciak, & Altar, 1995). The above effect is an example of positive feedback, where the end of the pathway helps to perpetuate the beginning of the pathway. Conversely, stress can significantly lower BDNF levels (Smith, Makino, Kvetnansky, & Post, 1995). In conclusion, the norepinephrine / cAMP / PKA pathway generally assumes a very positive role in mental health, the exception being when it is overstimulated in manic patients (Young et al., 1993). As mentioned earlier, the histamine H2 receptor is coupled to the cAMP pathway, and activation of the receptor raises cAMP levels.
The IP3/DAG pathway is significantly more complicated than the cAMP pathway. This is because there is not one main pathway, but two. Some would argue that it is a misnomer to call IP3/DAG a ‘pathway’, since the single pathway from the membrane receptor splits into two separate pathways very early on; one becoming the IP3 pathway, and the other becoming the DAG pathway. The model system for this hybrid pathway is the 5-HT2A receptor pathway. 5-hydroxytryptamine (5-HT, serotonin) binds to its 2A receptor, activating another G-protein, termed Gq that is different than the one in the norepinephrine receptor pathway. Gq then activates the enzyme phospholipase C (PLC). It is this enzyme that initiates the divergence of the serotonin signal by splitting the lipid-sugar phosphatidylinositol 4,5-bisphosphate (PIP2) into the aforementioned 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (De Chaffoy de Courcelles et al., 1985).
The DAG signal activates the enzyme protein kinase C (PKC) (Nishizuka, 1986). PKC performs a wide variety of functions. It plays a role in long-term changes in brain gene expression, neuronal excitation, and neurotransmitter release (Stabel & Parker, 1991). One of the more important PKC functions is to phosphorylate microtubule-associated protein 2 (MAP2) (Hoshi et al., 1988). Interestingly, PKA also appears to phosphorylate MAP2 (Sloboda, Rudolph, Rosenbaum, & Greengard, 1975). This is one of the ways that the cAMP and IP3/DAG pathways interact with each other.
However, an even more important interaction is that phosphorylated MAP2 inhibits microtubule assembly (Jameson et al., 1980). Microtubules form much of the cytoskeletal framework of the cell. Microtubules are formed by polymerization (multimerization) of tubulin dimers (two attached tubulin proteins). Tubulin dimers then stimulate adenylyl cyclase, the enzyme that is in the cAMP pathway (Hatta, Ozawa, Saito, & Ohshika, 1995). Thus, the DAG pathway feeds, or shunts, into the cAMP pathway. Many psychiatric and neurological researchers were perplexed for several years that antidepressants affecting either norepinephrine or serotonin reuptake both had very similar biochemical results. The discovery of the DAG shunt into the cAMP pathway elegantly resolves this former theoretical paradox.
The IP3 pathway is less straightforward than the DAG pathway. After being formed, IP3 then binds to an intracellular receptor that releases calcium ion (Ca2+). Ca2+ has many important actions within the cell. In this model, Ca2+ activates two main proteins, calmodulin (CaM), and calcineurin. These two downstream proteins of IP3 do not always have positive effects on well-being, as is normally the case for the cAMP and DAG pathway proteins. CaM activates a group of enzymes known as calmodulin kinases (CaM K’s). CaM K’s can interact with the cAMP pathway by influencing CREB-mediated transcription. As discussed earlier, CREB-mediated transcription has a positive effect on brain function. Some CaM K’s activate CREB (Anderson et al., 1998); other CaM K’s inhibit CREB (Hook & Means, 2001). Like the CaM K’s, calcineurin may activate or inhibit CREB (Schwaninger et al., 1995; Bito, Deisseroth, & Tsien, 1996). Histamine H1 receptors are linked to the IP3/Ca2+ pathway, and the DAG/PKC pathway (Wada,