Zia Rahman - Academia.edu (original) (raw)

Papers by Zia Rahman

Cellular Signalling, 2004

Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) fo... more Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) for Galpha subunits, attenuating G-protein-coupled receptor signal transduction. The present study tested the ability of members of different subfamilies of RGS proteins to modulate both G-protein-dependent and -independent signaling in mammalian cells. RGS4, RGS10, and RGSZ1 significantly attenuated Galphai-mediated signaling by 5-HT1A, but not by dopamine D2, receptor-expressing cells. Additionally, RGS4 and RGS10 significantly inhibited forskolin-stimulated cAMP production in both cell lines. In contrast, RGS2, RGS7, and RGSZ1 had no effect on forskolin-stimulated cAMP production in these cells. RGS2 and RGS7 significantly decreased Galphaq-mediated signaling by 5-HT2A receptors, confirming that the RGS4 and RGS10 effects on forskolin-stimulated cAMP production were specific, and not simply due to overexpression. Interestingly, similar expression levels of RGS4 protein resulted in greater inhibition of G-protein-independent cAMP production compared to G-protein-dependent GAP activity. Our results suggest specificity and selectivity of RGS proteins on G-protein-dependent and -independent signaling in mammalian cells.

Biological Psychiatry, 2001

Introduction: In the present study, we determined whether certain proteins known to mediate dopam... more Introduction: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson’s disease.Methods: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson’s disease and from control subjects. Levels of several markers of dopaminergic function were also assayed.Results: Levels of the transcription factor ΔFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson’s disease. Levels of several other proteins were not affected. Interestingly, levels of both ΔFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter.Conclusions: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of ΔFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in ΔFosB and RGS9 occur in humans with Parkinson’s disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson’s disease and assist in the development of novel treatments.

Neuron, 2003

neurons (Saugstad et al., 1998), the net effect of RGS California Institute of Technology protein... more neurons (Saugstad et al., 1998), the net effect of RGS California Institute of Technology proteins in an intact neural system remains largely unex-Pasadena, California 91125 plored. 5 Department of Pharmacology RGS proteins differ in their size, composition, and Virginia Commonwealth University tissue distribution, but all members contain a conserved, Richmond, Virginia 23298 approximately 120 amino acid sequence, referred to as 6 Department of Pharmacology and Neuroscience the RGS domain. Since their initial description, the RGS University of North Texas Health Science Center family of proteins has grown rapidly and includes homo-Fort Worth, Texas 76107 logs throughout the animal and fungal kingdoms (Ross 7 Department of Genetics and Wilkie, 2000). To date, at least 25 mammalian gene Harvard Medical School products containing the core RGS domain have been Belmont, Massachusetts 02478 identified. Numerous RGS genes are expressed in the brain with highly region-specific expression patterns (Gold et al., 1997). The expression pattern for one RGS family member, Summary RGS9, is particularly striking. The RGS9 gene gives rise to two products, RGS9-1 and RGS9-2, via alternative Regulators of G protein signaling (RGS) modulate hetsplicing (He et al., 1998; Rahman et al., 1999; Zhang et erotrimeric G proteins in part by serving as GTPaseal., 1999). Each splice variant displays highly specific activating proteins for G␣ subunits. We examined a and nonoverlapping tissue distribution. RGS9-1 is exrole for RGS9-2, an RGS subtype highly enriched in pressed exclusively in retina, while RGS9-2 is highly striatum, in modulating dopamine D2 receptor funcenriched in striatal regions of brain, which include dorsal tion. Viral-mediated overexpression of RGS9-2 in rat striatum (caudoputamen), ventral striatum (nucleus acnucleus accumbens (ventral striatum) reduced lococumbens), and olfactory tubercle, with very low levels motor responses to cocaine (an indirect dopamine agof expression seen throughout the rest of brain or in onist) and to D2 but not to D1 receptor agonists. Conperipheral tissues. The striatal-enriched expression of versely, RGS9 knockout mice showed heightened RGS9-2 and its localization in medium spiny projection locomotor and rewarding responses to cocaine and reneurons (Thomas et al., 1998) suggests that it has a role lated psychostimulants. In vitro expression of RGS9-2 in dopamine-mediated behavior. One feature of striatal in Xenopus oocytes accelerated the off-kinetics of D2 neurons is their rich innervation by dopamine and high receptor-induced GIRK currents, consistent with the levels of expression of dopamine receptors (Aizman et in vivo data. Finally, chronic cocaine exposure inal., 2000; Graybiel, 2000). D2 receptors in the nucleus creased RGS9-2 levels in nucleus accumbens. Together, accumbens are particularly important in mediating the these data demonstrate a functional interaction belocomotor-activating and rewarding effects of psychotween RGS9-2 and D2 receptor signaling and the bestimulant drugs of abuse, such as cocaine and amphethavioral actions of psychostimulants and suggest that amine (Self and Nestler, 1998; Wise, 1998; Koob, 1999).

European Journal of Neuroscience, 2002

Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, includ... more Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene. Analysis of this fragment revealed consensus elements for several transcription factors, including a canonical cAMP response element (CRE) in close proximity to the transcription initiation region. Next, ACVIII promoter activity was studied in two neural-derived cell lines and in primary cultures of rat striatal neurons. Activation of the cAMP pathway by forskolin treatment increased promoter activity, and a series of deletion and point mutants demonstrated that this activation is mediated speci®cally via the canonical CRE site. Gel shift assays con®rmed that this site can bind CREB and several CREB family proteins. Further, activation of the ACVIII promoter by forskolin was potentiated by expression of a constitutively active form of CREB, CREB-VP16, whereas it was inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally, over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII promoter activity in the brains of ACVIII-LacZ transgenic mice. These results suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that this regulation may contribute to CREB-dependent neural plasticity.

Morphine stimulates the internalization of -opioid receptors (MORs) in transfected cell models to... more Morphine stimulates the internalization of -opioid receptors (MORs) in transfected cell models to a lesser degree than opioid peptides and other analgesic drugs, such as methadone, and previous studies have reported that morphine does not produce a detectable redistribution of MORs in neural tissue after either acute or chronic administration. Nevertheless, morphine produces profound physiological effects, raising the question of whether receptor trafficking plays any role in the in vivo actions of morphine. We investigated the effects of opiate drugs on recombinant and native opioid receptors in the nucleus accumbens, which plays an important role in mediating the behavioral effects of opiate drugs.

Proceedings of The National Academy of Sciences, 2003

Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination ... more Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration.

Nano Letters, 2002

We synthesize, for the first time, using sol−gel technique and without doping any trivalent impur... more We synthesize, for the first time, using sol−gel technique and without doping any trivalent impurities, monodispersed, spherical ZrO 2 particles in size range of ∼500−600 nm, exhibiting metastable tetragonal crystal structure at room temperature. It is revealed using high-resolution transmission electron microscopy that "hard-aggregates" forming tendency of ZrO 2 nanocrystallites of size ∼45 nm is responsible for stabilizing the high-temperature metastable tetragonal phase, at room temperature, within large sized (∼500−600 nm) undoped ZrO 2 particles.

Sensors and Actuators B-chemical, 2003

Al 2 O 3 -ZrO 2 composite gel precursor powder containing 5-15 mol% ZrO 2 was prepared by wet che... more Al 2 O 3 -ZrO 2 composite gel precursor powder containing 5-15 mol% ZrO 2 was prepared by wet chemical route. The washed gel containing pseudoboehmite and amorphous zirconia was characterized with respect to DTA/TG, XRD and IR spectroscopy. The DTA/TG result indicates three-stage decomposition for pseudoboehmite and single stage decomposition for amorphous zirconia. In the calcined powder phase evolution of Al 2 O 3 follows the sequence pseudoboehmite ! bayerite ! boehmite ! g-Al 2 O 3 ! u-Al 2 O 3 ! a-Al 2 O 3 , while that of ZrO 2 follows amorphous ZrO 2 ! t-ZrO 2 ! (t + m)ZrO 2 . FTIR studies revealed that the number of M-OH and M-O bond increase on increasing mol% of ZrO 2 due to a change in the cationic charge of the composite powder. TEM photograph of calcined powder showed both dispersed nano-size spherical particle as well as agglomerated particles. EPMA confirmed the near uniform distribution of zirconia particles in the alumina matrix. #

Cellular Signalling, 2004

Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) fo... more Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) for Galpha subunits, attenuating G-protein-coupled receptor signal transduction. The present study tested the ability of members of different subfamilies of RGS proteins to modulate both G-protein-dependent and -independent signaling in mammalian cells. RGS4, RGS10, and RGSZ1 significantly attenuated Galphai-mediated signaling by 5-HT1A, but not by dopamine D2, receptor-expressing cells. Additionally, RGS4 and RGS10 significantly inhibited forskolin-stimulated cAMP production in both cell lines. In contrast, RGS2, RGS7, and RGSZ1 had no effect on forskolin-stimulated cAMP production in these cells. RGS2 and RGS7 significantly decreased Galphaq-mediated signaling by 5-HT2A receptors, confirming that the RGS4 and RGS10 effects on forskolin-stimulated cAMP production were specific, and not simply due to overexpression. Interestingly, similar expression levels of RGS4 protein resulted in greater inhibition of G-protein-independent cAMP production compared to G-protein-dependent GAP activity. Our results suggest specificity and selectivity of RGS proteins on G-protein-dependent and -independent signaling in mammalian cells.

Biological Psychiatry, 2001

Introduction: In the present study, we determined whether certain proteins known to mediate dopam... more Introduction: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson’s disease.Methods: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson’s disease and from control subjects. Levels of several markers of dopaminergic function were also assayed.Results: Levels of the transcription factor ΔFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson’s disease. Levels of several other proteins were not affected. Interestingly, levels of both ΔFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter.Conclusions: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of ΔFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in ΔFosB and RGS9 occur in humans with Parkinson’s disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson’s disease and assist in the development of novel treatments.

Neuron, 2003

neurons (Saugstad et al., 1998), the net effect of RGS California Institute of Technology protein... more neurons (Saugstad et al., 1998), the net effect of RGS California Institute of Technology proteins in an intact neural system remains largely unex-Pasadena, California 91125 plored. 5 Department of Pharmacology RGS proteins differ in their size, composition, and Virginia Commonwealth University tissue distribution, but all members contain a conserved, Richmond, Virginia 23298 approximately 120 amino acid sequence, referred to as 6 Department of Pharmacology and Neuroscience the RGS domain. Since their initial description, the RGS University of North Texas Health Science Center family of proteins has grown rapidly and includes homo-Fort Worth, Texas 76107 logs throughout the animal and fungal kingdoms (Ross 7 Department of Genetics and Wilkie, 2000). To date, at least 25 mammalian gene Harvard Medical School products containing the core RGS domain have been Belmont, Massachusetts 02478 identified. Numerous RGS genes are expressed in the brain with highly region-specific expression patterns (Gold et al., 1997). The expression pattern for one RGS family member, Summary RGS9, is particularly striking. The RGS9 gene gives rise to two products, RGS9-1 and RGS9-2, via alternative Regulators of G protein signaling (RGS) modulate hetsplicing (He et al., 1998; Rahman et al., 1999; Zhang et erotrimeric G proteins in part by serving as GTPaseal., 1999). Each splice variant displays highly specific activating proteins for G␣ subunits. We examined a and nonoverlapping tissue distribution. RGS9-1 is exrole for RGS9-2, an RGS subtype highly enriched in pressed exclusively in retina, while RGS9-2 is highly striatum, in modulating dopamine D2 receptor funcenriched in striatal regions of brain, which include dorsal tion. Viral-mediated overexpression of RGS9-2 in rat striatum (caudoputamen), ventral striatum (nucleus acnucleus accumbens (ventral striatum) reduced lococumbens), and olfactory tubercle, with very low levels motor responses to cocaine (an indirect dopamine agof expression seen throughout the rest of brain or in onist) and to D2 but not to D1 receptor agonists. Conperipheral tissues. The striatal-enriched expression of versely, RGS9 knockout mice showed heightened RGS9-2 and its localization in medium spiny projection locomotor and rewarding responses to cocaine and reneurons (Thomas et al., 1998) suggests that it has a role lated psychostimulants. In vitro expression of RGS9-2 in dopamine-mediated behavior. One feature of striatal in Xenopus oocytes accelerated the off-kinetics of D2 neurons is their rich innervation by dopamine and high receptor-induced GIRK currents, consistent with the levels of expression of dopamine receptors (Aizman et in vivo data. Finally, chronic cocaine exposure inal., 2000; Graybiel, 2000). D2 receptors in the nucleus creased RGS9-2 levels in nucleus accumbens. Together, accumbens are particularly important in mediating the these data demonstrate a functional interaction belocomotor-activating and rewarding effects of psychotween RGS9-2 and D2 receptor signaling and the bestimulant drugs of abuse, such as cocaine and amphethavioral actions of psychostimulants and suggest that amine (Self and Nestler, 1998; Wise, 1998; Koob, 1999).

European Journal of Neuroscience, 2002

Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, includ... more Adenylyl cyclase (AC) type VIII has been implicated in several forms of neural plasticity, including drug addiction and learning and memory. In the present study, we directly examined the role for the transcription factor CREB (cAMP response element binding protein) in regulating ACVIII expression by cloning a 5.2 kilobase region upstream of the translation start site of the mouse ACVIII gene. Analysis of this fragment revealed consensus elements for several transcription factors, including a canonical cAMP response element (CRE) in close proximity to the transcription initiation region. Next, ACVIII promoter activity was studied in two neural-derived cell lines and in primary cultures of rat striatal neurons. Activation of the cAMP pathway by forskolin treatment increased promoter activity, and a series of deletion and point mutants demonstrated that this activation is mediated speci®cally via the canonical CRE site. Gel shift assays con®rmed that this site can bind CREB and several CREB family proteins. Further, activation of the ACVIII promoter by forskolin was potentiated by expression of a constitutively active form of CREB, CREB-VP16, whereas it was inhibited by expression of a dominant-negative form of CREB, A-CREB. Finally, over-expression of CREB in vivo, by viral-mediated gene transfer, induced ACVIII promoter activity in the brains of ACVIII-LacZ transgenic mice. These results suggest that the ACVIII gene is regulated by CREB in vitro and in vivo and that this regulation may contribute to CREB-dependent neural plasticity.

Morphine stimulates the internalization of -opioid receptors (MORs) in transfected cell models to... more Morphine stimulates the internalization of -opioid receptors (MORs) in transfected cell models to a lesser degree than opioid peptides and other analgesic drugs, such as methadone, and previous studies have reported that morphine does not produce a detectable redistribution of MORs in neural tissue after either acute or chronic administration. Nevertheless, morphine produces profound physiological effects, raising the question of whether receptor trafficking plays any role in the in vivo actions of morphine. We investigated the effects of opiate drugs on recombinant and native opioid receptors in the nucleus accumbens, which plays an important role in mediating the behavioral effects of opiate drugs.

Proceedings of The National Academy of Sciences, 2003

Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination ... more Regulators of G protein signaling (RGS) are a family of proteins known to accelerate termination of effector stimulation after G protein receptor activation. RGS9-2, a brain-specific splice variant of the RGS9 gene, is highly enriched in striatum and also expressed at much lower levels in periaqueductal gray and spinal cord, structures known to mediate various actions of morphine and other opiates. Morphine exerts its acute rewarding and analgesic effects by activation of inhibitory guanine nucleotide-binding regulatory protein-coupled opioid receptors, whereas chronic morphine causes addiction, tolerance to its acute analgesic effects, and profound physical dependence by sustained activation of these receptors. We show here that acute morphine administration increases expression of RGS9-2 in NAc and the other CNS regions, whereas chronic exposure decreases RGS9-2 levels. Mice lacking RGS9 show enhanced behavioral responses to acute and chronic morphine, including a dramatic increase in morphine reward, increased morphine analgesia with delayed tolerance, and exacerbated morphine physical dependence and withdrawal. These findings establish RGS9 as a potent negative modulator of opiate action in vivo, and suggest that opiate-induced changes in RGS9 levels contribute to the behavioral and neural plasticity associated with chronic opiate administration.

Nano Letters, 2002

We synthesize, for the first time, using sol−gel technique and without doping any trivalent impur... more We synthesize, for the first time, using sol−gel technique and without doping any trivalent impurities, monodispersed, spherical ZrO 2 particles in size range of ∼500−600 nm, exhibiting metastable tetragonal crystal structure at room temperature. It is revealed using high-resolution transmission electron microscopy that "hard-aggregates" forming tendency of ZrO 2 nanocrystallites of size ∼45 nm is responsible for stabilizing the high-temperature metastable tetragonal phase, at room temperature, within large sized (∼500−600 nm) undoped ZrO 2 particles.

Sensors and Actuators B-chemical, 2003

Al 2 O 3 -ZrO 2 composite gel precursor powder containing 5-15 mol% ZrO 2 was prepared by wet che... more Al 2 O 3 -ZrO 2 composite gel precursor powder containing 5-15 mol% ZrO 2 was prepared by wet chemical route. The washed gel containing pseudoboehmite and amorphous zirconia was characterized with respect to DTA/TG, XRD and IR spectroscopy. The DTA/TG result indicates three-stage decomposition for pseudoboehmite and single stage decomposition for amorphous zirconia. In the calcined powder phase evolution of Al 2 O 3 follows the sequence pseudoboehmite ! bayerite ! boehmite ! g-Al 2 O 3 ! u-Al 2 O 3 ! a-Al 2 O 3 , while that of ZrO 2 follows amorphous ZrO 2 ! t-ZrO 2 ! (t + m)ZrO 2 . FTIR studies revealed that the number of M-OH and M-O bond increase on increasing mol% of ZrO 2 due to a change in the cationic charge of the composite powder. TEM photograph of calcined powder showed both dispersed nano-size spherical particle as well as agglomerated particles. EPMA confirmed the near uniform distribution of zirconia particles in the alumina matrix. #