Second messengers gene transcription

Another type of NR crosstalk, which has only recently been recognized, is the so-called nongenomic actions of several receptors that induce very rapid cellular effects. Effectively, evidence has accumulated over several decades that steroid receptors may have a role that does not require their transcriptional activation, such as modifying the activity of enzymes and ion channels. While the effects of steroids that are mediated by the modulation of gene expression do occur with a time lag of hours, steroids can induce an increase in several second messengers such as inositol triphosphate, cAMP, Ca2+, and the activation of MARK and PI3 kinase within seconds or minutes. Many mechanistic details of these nongenomic phenomena remain poorly understood. Notably, controversy still exists as to the identity of the receptors that initiate the non-genomic steroid actions. However, it now appears that at least some of the reported effects can be attributed to the same steroid receptors that are known as NRs. 

The regulation of receptor synthesis is a second component of receptor downregulation. It involves processes that reduce gene transcription, mRNA stability, and receptor half-life time. It should be noted that mechanisms in addition to the regulation of the receptor number may account for tolerance development. Second messenger levels and enzyme activities that participate in the signaling of a given receptor are... 

The possible combinations generated by these mechanisms could be sufficient to account for ligand-specific and cell-specific biological responses, notwithstanding the limited number of second messengers that are available for the transcription of the primary response genes (Herschman, 1989). It is apparent that much remains to be done to understand the complexity of the cytoskeleton and its interactions within cells and across cell membranes. 

The interaction of external signals with membrane receptors generates second messengers. These messengers either modify the cell concentration of ions or metabolites or alter the functional state of a chain of several molecules that act as intermediaries. These intermediaries may modify the intensity of determined biochemical reactions or, in other cases, are integrated into the machinery of gene transcription and alter the expression of specific genes. The consequences of these activities can lead to the induction of cell division. 

Figure 12-5. Transcriptional control by CREB. Cyclic AMP is a second messenger that mediates signaling from cell-surface receptors to elicit a response from the cell, in this case, a change in expression of genes that have a cyclic AMP response element (CRE) by binding of activated CREB.

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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