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M Memo

Publications and source records attributed to M Memo.

134 records · Page 8Linked to original sources
PubMedDate not supplied

Pharmacological and molecular basis for dopamine D-2 receptor diversity.

This review will focus on the main lines of evidence that suggest the existence of multiple types of dopamine D-2 receptors. Dopamine D-2 receptors share structural elements suggesting that they belong to a gene superfamily classified as G-protein-coupled receptors and show an archetypical topology predicted to consist of seven putative transmembrane domains. Activation of D-2 receptors results in a variety of responses, including inhibition of cyclic AMP formation, inhibition of phosphoinositol turnover, increase of K-channel activity, and inhibition of Ca influx. The G protein(s) linking the D-2 receptors to these responses have not been completely identified, nor has the possible hierarchy of these regulatory proteins in transforming the incoming signal into a change of second-messenger levels. A lot of experimental data support the hypothesis that there are multiple signal-processing pathways activated by dopamine through D-2-receptor stimulation. Recently, the identification of dopaminergic drugs that discriminate among the different transduction pathways and the isolation of distinct cDNAs encoding proteins that share binding profile indicative of D-2 receptors clearly indicate multiple forms of D-2 receptors. Pharmacologically, at least two distinct categories of dopamine D-2 receptors exist in rat pituitary. The first (D-2a) is insensitive to BHT 920 and coupled to inhibition of adenylyl cyclase activity; the second (D-2b) is activated by BHT 920 and linked to voltage-dependent K channels. The two types of dopamine D-2 receptors differ in their structure, G-protein-coupled and effector. Each of the three basic receptor units shows a certain degree of heterogeneity, which may affect the quality and the kinetic of the response. This variety may represent the molecular basis for the diversity in pharmacological and functional profiles of different dopamine D-2 receptors located in various brain areas and peripheral tissues.

Adenylyl Cyclase Inhibitors↗
PubMedDate not supplied

Dopamine D2, D3, and D4 receptor mRNA levels in rat brain and pituitary during aging.

Reverse Transcriptase-Polymerase Chain Reaction technique was used to determine the levels of the mRNAs encoding different receptors belonging to the D2 family in various brain areas of 6-, 12-, 18-, and 24-month-old rats. We found a progressive, age-dependent reduction in the mRNA levels of D2 short and D2 long receptors in corpus striatum, substantia nigra, and frontal cortex. D2 short and D2 long receptor mRNA levels were unchanged in hippocampus and olfactory tubercle, while they increased in pituitary. D3 receptor mRNA levels were reduced in olfactory tubercle and unchanged in striatum. D4 receptor mRNA levels were unmodified in pituitary gland. These data suggest that the molecular mechanisms responsible for regulating the pattern of expression of the various dopamine receptors are differentially regulated by aging.

Aging↗
PubMedDate not supplied

Chronic lead treatment differentially affects dopamine synthesis in various rat brain areas.

The effect of chronic dietary lead exposure on brain nigrostriatal, mesolimbic and mesocortial systems was studied. The results show no modification of the dopamine receptors measured either as dopamine sensitive adenylate cyclase or as [3H]spiroperidol binding. On the other hand, dopamine synthesis seems to be reduced in striatum, unaffected in substantia nigra and increased in nucleus accumbens and in the frontal cortex. The increase of DA synthesis observed in some brain areas might be involved in determining the hyperactive behaviour that follows lead intoxication.

Adenylyl Cyclases↗
PubMedDate not supplied

Contribution of NF-kappaB and p53 in the glutamate-induced apoptosis.

Exposure of primary cultures of cerebellar granule cells for 15 min to micromolar concentrations of glutamate results in cell death of both necrotic and apoptotic types. Among the intracellular events triggered by glutamate, we identified two transcriptional factors: the p50 member of the NF-kappaB family and the tumor suppressor phosphoprotein p53. Pretreatment of the cultures with aspirin, which inhibits NF-kappaB activation, or with specific p53 antisense oligonucleotide, which inhibits p53 transcription, resulted in a complete prevention of glutamate-induced p53 induction and apoptosis. These findings suggest the existence of a transcriptional program activated by glutamate receptor stimulation in which p50 and p53 play a relevant role. Then, we studied the expression of two p53 downstream genes that could participate in the glutamate-induced pro-apoptotic pathway: p21, which codes for an inhibitor of different cyclin dependent kinases, and MSH2, which codes for a protein involved in the recognition and repair of DNA mismatches. We found that primary cerebellar neurons expressed p21 and MSH2 at very low levels in basal conditions. However, very soon after a brief exposure of the cells to glutamate, the expression of both proteins was dramatically enhanced.On these bases, we propose NF-kappaB, p53, p21 and MSH2 as relevant contributors of the glutamate-induced pro-apoptotic pathway. Understanding this cascade of nuclear events may unravel specific targets for pharmacological intervention for those neurological diseases in which excitatory amino acid-induced apoptosis plays a relevant role.

Aging↗