| Popis: |
Numerous changes in neuronal activity have been documented to be under the control of dopaminergic systems. Prominent among these are changes in transcription of neurotransmitter genes which are expressed in dopamine receptor positive neurons throughout the brain. The dopamine receptors are subdivided in two subfamilies: the D1-like (D1, D5) and the D2-like (D2, D3, D4).* As described in Chapter 6, members of this class of receptors are either positively or negatively coupled to some of the most important signal transduction pathways involved in regulating gene transcription. Prominent among these is the adenylate cyclase—cyclic adenosine monophosphate (cAMP) system, in which the cascade of events leading to gene transcription has in large part been elucidated. Agonism of receptors positively or negatively coupled to adenylate cyclase alters the conversion of ATP to cAMP. Subsequent binding of this nucleotide to the regulatory subunit of protein kinase A (PKA) leads to activation of its catalytic domain which carries out phosphorylation of numerous neuronal proteins. Among these downstream, rapid signaling events is the phosphorylation of a protein termed the cAMP response element-binding protein or CREB. Phosphorylation on a serine residue in position 133 of this protein enhances its ability to promote gene transcription. CREB binds as a dimer to a canonical sequence of nucle-otides termed the cAMP response element (CRE) found in the upstream 5′ flanking region of numerous genes. Interestingly, this element is found in the promoter regions of genes encoding other transcriptional activators such as members of the immediate-early gene family, including c-fos. Thus agonism or antagonism of any given dopamine receptor can (as is described in Section 3.) and does lead to induction of a variety of factors capable of influencing transcription of neurotransmitter genes, such as those encoding the neuropeptides enkephalin and neurotensin. |
