Nicotine regulates nicotinic cholinergic receptors and subunit rnRNAs in PC 12 cells through protein kinase A

Madhok, Thelma C.; Matta, Shannon G.; Sharp, Burt M.

doi:10.1016/0169-328x(95)00073-2

Cited by 22 publications

(13 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pretreatment with the adenylyl cyclase inhibitor 2Ј,5Ј-dideoxyadenosine (DDA) prevented both the nicotine-elicited phosphorylation of CREB and the subsequent induction of TH mRNA (15). PKA-deficient PC12 cells treated with nicotine were unable to support many of the alterations in gene expression observed in normal cells, including the elevation of TH mRNA levels (6,40). The possible mechanism whereby activation of CaMKs regulates the expression of target genes is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Prolonged Activation of cAMP-response Element-binding Protein and ATF-2 Needed for Nicotine-triggered Elevation of Tyrosine Hydroxylase Gene Transcription in PC12 Cells

Gueorguiev

Cheng

Sabban

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Phosphorylation (P-) of cAMP-response element-binding protein (CREB) by protein kinase A or mitogen-activated protein kinases was implicated in mediating the increased tyrosine hydroxylase (TH) gene expression after prolonged exposure to nicotine in vivo and in cell culture. We examined the time course and signaling pathways for phosphorylation of CREB and possible involvement of ATF-2. Treatment of PC12 cells with 200 M nicotine triggered rapid but transient elevation of P-CREB followed by a second sustained rise after 2-5 h of continuous nicotine. In contrast, ERK1/2 was only phosphorylated with short term nicotine exposure. MEK inhibitor U0126 abolished nicotine-induced rise in P-ERK1/2, but not P-CREB, nor did it inhibit nicotine-evoked elevation in TH promoter activity, indicating that ERK1/2 was not needed for induction of TH gene expression by nicotine. In contrast, protein kinase A inhibitor H-89 or Ca 2؉ / calmodulin-activated protein kinase inhibitor KN-93 reduced the nicotine-triggered rise in P-CREB and TH promoter activity. There was a delayed elevation of P-ATF-2 after 1 h of nicotine treatment, accompanied by increased ATF-2 protein. Upstream kinase JNK, but not p38, was phosphorylated especially after 5 min to 2 h of nicotine exposure. To examine the requirement for CREB and ATF-2, cells were transfected with dominant negative forms of ATF-2 or CREB. Both reduced the basal TH promoter activity and the response to nicotine. Knockdown of ATF-2 or CREB with siRNA did not alter basal TH promoter activity or mRNA but greatly attenuated the response to nicotine. The results suggest that both ATF-2 and CREB mediate activation of TH gene transcription by nicotine.Administration of nicotine in vivo and in cell culture triggers increased expression of a number of genes related to neurosecretion including the catecholamine biosynthetic enzymes. These changes in gene expression may be involved in neurochemical and cardiovascular effects of smoking. Nicotine is a potent sympathomimetic agent, and its administration, in doses similar to those obtained in smoking, increases heart rate and systolic and diastolic blood pressure in humans and many animal species (for review, see Ref. 1). These cardiovascular effects are largely attributed to the direct stimulation of release of catecholamines, epinephrine and norepinephrine, from the adrenal medulla and peripheral sympathetic nerve endings (2-4). In this regard a polymorphism in the gene for tyrosine hydroxylase (TH), 2 the rate-limiting enzyme in catecholamine biosynthesis, has been associated with tobacco use (5).Transcriptional mechanisms are at least partially responsible for the nicotine triggered changes in TH gene expression. The response of TH to nicotine has been proposed to be mediated by CREB. Nicotine treatment both in vivo and in vitro induces phosphorylation of CREB (6 -8).The cAMP/calcium response element (CRE/CaRE) in the TH promoter is required for its transcriptional activation by nicotine in PC12 cells (6). CREB is activated through the phosphor...

show abstract

Section: Discussionmentioning

confidence: 99%

Prolonged Activation of cAMP-response Element-binding Protein and ATF-2 Needed for Nicotine-triggered Elevation of Tyrosine Hydroxylase Gene Transcription in PC12 Cells

Gueorguiev

Cheng

Sabban

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Furthermore, NGF has also been reported to increase Henderson et al, 1994;Hu et al, 1994;Takahashi et al, 1999;Nakayama et al, 2000) as well as decrease mRNA encoding certain nAChR subunits in PC12 cells. In addition, both nicotine and NGF treatment have been reported to increase [ 3 H]nicotine binding sites in these cells (Madhok and Sharp, 1992;Madhok et al, 1995 3 H]EB in PC12 cells. We determined whether these two treatments affected the same or different receptor subtypes, characterized these subtypes with respect to their pharmacology, and determined how each treatment affected receptor functions.…”

mentioning

confidence: 99%

Differential Regulation of Nicotinic Acetylcholine Receptors in PC12 Cells by Nicotine and Nerve Growth Factor

Avila

Dávila‐García²,

Ascarrunz³

et al. 2003

Mol Pharmacol

View full text Add to dashboard Cite

ABSTRACT3 H]epibatidine were found: one that was increased about 4-fold in cells grown for 2 to 4 days in the presence of nicotine and one that was increased 5-fold in cells grown for 2 to 4 days in the presence of nerve growth factor (NGF). The actions of the two treatments were superadditive, resulting in approximately a 13-fold increase in binding sites in cells grown in the combination of the two treatments. The pharmacology of the binding sites in the nicotine-and NGF-treated cells was compared with the pharmacology of defined ␣3␤2 and ␣3␤4 nicotinic acetylcholine receptor (nAChR) subtypes heterologously expressed in human embryonic kidney 293 cells. Nicotine treatment predominantly increased a receptor with characteristics of an ␣3␤2 subtype, whereas the NGF treatment exclusively increased a receptor with characteristics of an ␣3␤4 subtype. Nicotinic receptormediated function measured with the 86 Rb ϩ efflux assay was evident only in the NGF-treated cells, and it had a pharmacological profile that was, again, nearly identical to that of the heterologously expressed ␣3␤4 receptor subtype. Receptor function measured with the [ 3 H]norepinephrine release assay was measurable in both nicotine-treated and NGF-treated cells; however, cytisine-stimulated [ 3 H]norepinephrine release indicated that nicotine treatment increased an nAChR containing ␤2 subunits, whereas NGF increased a receptor containing ␤4 subunits. NGF treatment increased mRNA only for ␤4 subunits in these cells, whereas nicotine treatment did not affect mRNA for any of the subunits measured. After withdrawal of the treatments, the receptors increased by nicotine were much less stable than those increased by NGF.Neuronal nicotinic acetylcholine receptors (nAChRs) are found throughout the central nervous system as well as in autonomic ganglia and the adrenal gland, where they mediate cholinergic neurotransmission critical to the functions of the autonomic nervous system. These receptors are composed of two types of subunits, ␣ and ␤. To date, nine neuronal ␣ subunit genes (␣2-␣10) and three ␤ subunit genes (␤2-␤4) have been found in vertebrate tissues. Different combinations of subunits compose subtypes of nicotinic receptors, all of which are ligand-gated cation channels that conduct Na ϩ , K ϩ , and Ca 2ϩ when activated by the endogenous neurotransmitter acetylcholine or by nicotine or other nicotinic agonists. However, the different receptor subtypes have distinguishing biophysical and/or pharmacological properties, including channel conductances, rates of desensitization and recovery, and sensitivity to drugs (for reviews, see Sargent, 1993;Colquhoun and Patrick, 1997;Lukas, 1998).Certain subtypes of nAChRs are strongly regulated by nicotine. Previous studies have shown that chronic administration of nicotine increases nicotinic receptor binding sites in rat and mouse brain (Schwartz and Kellar, 1983;Marks et al., 1983; for review, see Gentry and Lukas, 2002), and a similar increase is found in human brains from people who smoked tobacco (Benwe...

show abstract

“…Chronic nicotine exposure caused an increase in the amount of [ 3 H]-nicotine binding in wild-type PC12 cells, which did not involve protein synthesis. This effect could be mimicked by an increase in intracellular cAMP; however, in mutant cells deficient in PKA, no increase in binding was seen (Madhok et al 1994(Madhok et al , 1995. Functional down-regulation of a4b2 nAChRs in permanently transfected HEK 293 cells, in response to chronic nicotine exposure, was mediated by downregulation of PKC activity.…”

Section: Modulation By Protein Kinasesmentioning

confidence: 77%

Nicotinic acetylcholine receptors: from structure to brain function

Hogg

Raggenbass

Bertrand

Reviews of Physiology, Biochemistry and Pharmacology

454

370

View full text Add to dashboard Cite

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and can be divided into two groups: muscle receptors, which are found at the skeletal neuromuscular junction where they mediate neuromuscular transmission, and neuronal receptors, which are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. nAChRs are pentameric structures that are made up of combinations of individual subunits. Twelve neuronal nAChR subunits have been described, alpha2-alpha10 and beta2-beta4; these are differentially expressed throughout the nervous system and combine to form nAChRs with a wide range of physiological and pharmacological profiles. The nAChR has been proposed as a model of an allosteric protein in which effects arising from the binding of a ligand to a site on the protein can lead to changes in another part of the molecule. A great deal is known about the structure of the pentameric receptor. The extracellular domain contains binding sites for numerous ligands, which alter receptor behavior through allosteric mechanisms. Functional studies have revealed that nAChRs contribute to the control of resting membrane potential, modulation of synaptic transmission and mediation of fast excitatory transmission. To date, ten genes have been identified in the human genome coding for the nAChRs. nAChRs have been demonstrated to be involved in cognitive processes such as learning and memory and control of movement in normal subjects. Recent data from knockout animals has extended the understanding of nAChR function. Dysfunction of nAChR has been linked to a number of human diseases such as schizophrenia, Alzheimer's and Parkinson's diseases. nAChRs also play a significant role in nicotine addiction, which is a major public health concern. A genetically transmissible epilepsy, ADNFLE, has been associated with specific mutations in the gene coding for the alpha4 or beta2 subunits, which leads to altered receptor properties

show abstract

Nicotine regulates nicotinic cholinergic receptors and subunit rnRNAs in PC 12 cells through protein kinase A

Cited by 22 publications

References 23 publications

Prolonged Activation of cAMP-response Element-binding Protein and ATF-2 Needed for Nicotine-triggered Elevation of Tyrosine Hydroxylase Gene Transcription in PC12 Cells

Prolonged Activation of cAMP-response Element-binding Protein and ATF-2 Needed for Nicotine-triggered Elevation of Tyrosine Hydroxylase Gene Transcription in PC12 Cells

Differential Regulation of Nicotinic Acetylcholine Receptors in PC12 Cells by Nicotine and Nerve Growth Factor

Nicotinic acetylcholine receptors: from structure to brain function

Contact Info

Product

Resources

About