CREB Function in Brain

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CREB is expressed in almost all mammalian cells and is a transcription factor with important functions in many tissues, including brain. It harbors an N-terminal activation domain and C-terminal DNA-binding dimerization domain (Fig. 2) and is a member of the basic leucine zipper (bZIP) protein superfamily. CREB is able to either

From: Molecular Biology of Drug Addiction Edited by: R. Maldonado © Humana Press Inc., Totowa, NJ

Fig. 1. The opiate signal transduction pathway. Opiates such as morphine bind to Gr or Go-coupled opioid receptors. Acute opiate exposure results in adenyl cyclase inhibition, reduction in cAMP levels and cAMP-dependent protein kinase activity and the phosphorylation of both cytoplasmic and nuclear targets, including CREB. On the other hand, chronic opiate exposure increases the levels of these factors.

Fig. 1. The opiate signal transduction pathway. Opiates such as morphine bind to Gr or Go-coupled opioid receptors. Acute opiate exposure results in adenyl cyclase inhibition, reduction in cAMP levels and cAMP-dependent protein kinase activity and the phosphorylation of both cytoplasmic and nuclear targets, including CREB. On the other hand, chronic opiate exposure increases the levels of these factors.

CREB protein

Transactivation DNA bind/Dimenzation Q1 KID Q2 basic L-Zip

Ser 133

10 11

Ser 133

10 11

ATG neo

hypomorph Viable

conditional null Viable

CREBnuI

null Lethal

Fig. 2. Functional domains of CREB include the C-terminal transactivation composed of two glutamine-rich domains (Q1 and Q2) flanking the kinase inducible domain (KID), which harbors serine residue 133 which is phosphorylated upon cellular stimulation via the cAMP pathway as well as other signaling pathways. The C-terminal domain harbors the basic leucine zipper (L-Zip) domains, which are involved in DNA binding and dimerization. The CREB gene is comprised by at least 11 exons shown as rectangles (white for untranslated and gray for translated). The three genetically modified CREB mutant mice generated in our laboratory are indicated with the disrupted exons shown. The only genetically modified CREB mutant mice that are viable are the CREBaD and the conditional CREBloxP mice. These have been used in drug studies described elsewhere (8,9) and herein.

homodimerize or heterodimerize with its closely related factors, CREM and ATF1 (10). Upon phosphorylation on a critical serine-133 residue, it can bind to cAMP-responsive elements (CREs) and recruit the CREB-binding protein (CBP) and other transcriptional cofactors to transactivate a large number of target genes important for cellular function (Fig. 1). Apart from CREB's role in the cellular responses triggered by drugs of abuse, specific functions attributed to CREB in brain include neuronal survival (11,12), hypothalamic/pituitary growth axis (13), circadian rhythm (14-16), and learning and memory (17,18).

Several molecular changes have been described during exposure to opioids (19-22). Acute opioid administration inhibits adenylyl cyclase activity, whereas chronic opioid treatment leads to a dramatic upregulation of the cAMP pathway at every major step of the cascade between receptor activation and physiological response (23) (Fig. 1). This upregulation occurs in discrete brain areas including the locus coeruleus (LC) and the nucleus accumbens (NAc), providing a neuroanatomical link for opioid physical dependence and rewarding effects, respectively (24-26) Upregulation of the cAMP pathway also seems to be involved in the addictive mechanisms of other drugs of abuse, such as cocaine (23,27). The phosphorylation state of CREB was shown to be decreased in the LC after acute morphine administration, whereas chronic morphine produces an increase in the phosphorylation and expression of CREB in this structure (5-7). We have previously demonstrated that CREB is an important factor involved in the onset of behavioral manifestations of opiate withdrawal, where the major signs of morphine abstinence were strongly attenuated in CREBm mutant mice, which lack the major transactivating CREB □ and □ isoforms (8) (see Section 3.). Work utilizing antisense oligonucleotides has also implicated decreased CREB expression in the LC with attenuated withdrawal and electrophysiological responses (7). CREB has also been implicated in the motivational properties of morphine and cocaine (27,28), although the functional relevance in molecular genetic animal models has not yet been determined.

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