Transcription factors second messengers

Although details will vary, in each case an agonist at its receptor activates adenylate cyclase and the second messenger cAMP is produced from ATP. cAMP activates protein kinase A and a cascade of reactions may follow. These may be metabolic reactions, as in the cases just described, or activation of a cAMP response-element protein, CREB. CREB is a transcription factor with affinity for specific sites on DNA. Control of protein synthesis follows. 

TTie second messenger, for example cyclic adenosine monophosphate (cAMP), then activates cAMP-dependent protein kinase which modulates the function of a broad range of membrane receptors, intracellular enzymes, ion channels and transcription factors. 

Action. cAMP is an allosteric effector of protein kinase A (PK-A, [3]). in the inactive state, PK-A is a heterotetramer (C2R2), the catalytic subunits of which (C) are blocked by regulatory units (R autoinhibition). When cAMP binds to the regulatory units, the C units separate from the R units and become enzymatically active. Active PK-A phosphorylates serine and threonine residues of more than 100 different proteins, enzymes, and transcription factors, in addition to cAMP, cCMP also acts as a second messenger, it is involved in sight (see p. 358) and in the signal transduction of NO (see p. 388). 

The substrates of the MAP kinase pathway are very diverse and include both cytosolic and nuclear localized proteins. Phospholipase A2 and transcription factors of the Ets family are well characterized substrates of the ERK pathway. Phosphorylation of a Ser residue of phospholipase A2 by ERK proteins leads to activation of the lipase activity. Consequently, there is an increase in release of arachidonic acid and of lyso-phospholipids, which can act immediately as diffusible signal molecules or may represent first stages in the formation of second messenger molecules. 

Chemical neurotransmission can be described more completely as a team of molecular players. The neurotransmitter may be the captain of the team, but it is only one key player. Other molecular players on the synaptic transmission team include the specific ions (Fig. 2—8), that interact with the ion channels (e.g., Fig. 2—6), various enzymes (Fig 2—9), transport carriers (Fig. 2—10), active transport pumps (Fig. 2—11), second messengers (Fig. 2—12), receptors (Fig. 2—13), transcription factors (Fig. 2—14), genes (Fig. 2—15), and gene products (Fig. 2—16). 

The molecular players beyond the second messenger are particularly important in gene regulation. They include both active and inactive forms of protein kinase, an enzyme that phosphorylates various intracellular proteins, and protein dephosphatase enzymes, which reverse this (Fig. 2—9). Also included are transcription factors, which... 

Perhaps a similar situation exists for depression due to a hypothesized problem within the molecular events distal to the receptor. Thus, second messenger systems leading to the formation of intracellular transcription factors that control gene regulation could be the site of deficient functioning of monoamine systems. This is the subject of much current research into the potential molecular basis of affective disorders. This hypothesis suggests some form of molecularly mediated deficiency in monoamines that is distal to the monoamines themselves and their receptors despite apparently normal levels of monoamines and numbers of monoamine receptors. 

Stahl, S.M. (1999) Molecular neurobiology for practicing psychiatrists, part 3 how second messengers turn on genes by activating protein kinases and transcription factors. /o r-nal of Clinical Psychiatry 60(11), 731-2. 

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