Nicotinic receptor partial agonists alter catecholamine homeostasis and response to nicotine in PC12 cells

Turcanu, D.S.; Kirtok, Necla; Eibl, Christoph; Guendisch, Daniela; LaGamma, Edmund F.; Nankova, Bistra B.

doi:10.1016/j.neulet.2012.03.088

Cited by 5 publications

(6 citation statements)

References 33 publications

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“…Previously, in PC12 cells (a rat pheochromocytoma tissue culture model of adrenal chromaffin cell functions), we showed that cytisine exhibits typical partial agonist properties at native coexisting ␣3␤4 and ␣7 nAChR with regard to its effects on catecholamine secretion and synthesis (44). In the present report, we aimed to compare the effects of cytisine and the full agonist nicotine on epinephrine secretion and their ability to alter TH mRNA levels in vivo.…”

Section: Experimental Designmentioning

confidence: 86%

“…Plasma glucagon, insulin, and corticosterone were determined using commercially available radioimmunoassay kits from Linco Research (St. Charles, MO) and Diagnostic Products (Los Angeles, CA) (8). Plasma epinephrine and norepinephrine concentrations were determined using a competitive enzyme immunoassay (Rocky Mountain Diagnostics, Colorado Springs, CO) as described (44).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, in PC12 cells (44) and in perfused adrenal glands, cytisine stimulates catecholamine release in a dose-, time-, and Ca 2ϩ -dependent manner (27,49) and blocks the actions of acetylcholine on nicotinic receptors through a competitive mechanism (32).…”

Section: Transsynaptic Modulationmentioning

confidence: 99%

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Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

LaGamma

Kirtok

Chan

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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LaGamma EF, Kirtok N, Chan O, Nankova BB. Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats. Am J Physiol Endocrinol Metab 307: E580 -E588, 2014. First published August 12, 2014; doi:10.1152/ajpendo.00237.2014.-Recurrent exposure to hypoglycemia can impair the normal counterregulatory hormonal responses that guard against hypoglycemia, leading to hypoglycemia unawareness. This pathological condition known as hypoglycemia-associated autonomic failure (HAAF) is the main adverse consequence that prevents individuals with type 1 diabetes mellitus from attaining the long-term health benefits of tight glycemic control. The underlying molecular mechanisms responsible for the progressive loss of the epinephrine response to subsequent bouts of hypoglycemia, a hallmark sign of HAAF, are largely unknown. Normally, hypoglycemia triggers both the release and biosynthesis of epinephrine through activation of nicotinic acetylcholine receptors (nAChR) on the adrenal glands. We hypothesize that excessive cholinergic stimulation may contribute to impaired counterregulation. Here, we tested whether administration of the nAChR partial agonist cytisine to reduce postganglionic synaptic activity can preserve the counterregulatory hormone responses in an animal model of HAAF. Compared with nicotine, cytisine has limited efficacy to activate nAChRs and stimulate epinephrine release and synthesis. We evaluated adrenal catecholamine production and secretion in nondiabetic rats subjected to two daily episodes of hypoglycemia for 3 days, followed by a hyperinsulinemic hypoglycemic clamp on day 4. Recurrent hypoglycemia decreased epinephrine responses, and this was associated with suppressed TH mRNA induction (a measure of adrenal catecholamine synthetic capacity). Treatment with cytisine improved glucagon responses as well as epinephrine release and production in recurrently hypoglycemic animals. These data suggest that pharmacological manipulation of ganglionic nAChRs may be promising as a translational adjunctive therapy to avoid HAAF in type 1 diabetes mellitus.hypoglycemia-associated autonomic failure; tyrosine hydroxylase; epinephrine release; cytisine; partial nicotinic acetylcholine receptor agonists AN ATTENUATED SYMPATHOADRENAL RESPONSE following recurrent exposure to hypoglycemia results in a pathological inability to recover from low blood glucose levels, contributes to patient unawareness of hypoglycemia, and is associated with increased mortality in type 1 and possibly type 2 diabetic patients, a condition known as hypoglycemia-associated autonomic failure (HAAF) (1, 11). HAAF is recognized as a major public health problem for patients with diabetes. It can also be induced in healthy subjects, in infants and in animal models suggesting it may involve a maladaptive response to repeated stress (9,12,14,20).Despite the well-established role of hypoglycemia per se in the development of HAAF, the mechanism(s) underlying the key feature of t...

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Section: Experimental Designmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

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Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

LaGamma

Kirtok

Chan

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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show abstract

“…For measurement of catecholamine concentration, serum samples were analyzed using a competitive enzyme immunoassay (Rocky Mountain Diagnostics, Colorado Springs, CO) as described (Turcanu et al. ; LaGamma et al. ).…”

Section: Methodsmentioning

confidence: 99%

“…Plasma hormone concentrations (glucagon, insulin, and corticosterone) were determined using commercially available radioimmunoassay kits from Linco Research, St. Charles, MO and Diagnostic Products, Los Angeles, CA . For measurement of catecholamine concentration, serum samples were analyzed using a competitive enzyme immunoassay (Rocky Mountain Diagnostics, Colorado Springs, CO) as described (Turcanu et al 2012;LaGamma et al 2014…”

Section: Hormone Analysesmentioning

confidence: 99%

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia

et al. 2015

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Acute metabolic stress such as insulin-induced hypoglycemia triggers a counterregulatory response during which the release of catecholamines (epinephrine), the activation of tyrosine hydroxylase (TH) enzyme and subsequent compensatory catecholamine biosynthesis occur in the adrenal medulla. However, recurrent exposure to hypoglycemia (RH), a consequence of tight glycemic control in individuals with type 1 and type 2 diabetes compromises this physiological response. The molecular mechanisms underlying the maladaptive response to repeated glucose deprivation are incompletely understood. We hypothesize that impaired epinephrine release following RH reflects altered regulation of adrenal catecholamine biosynthesis. To test this hypothesis, we compared the effect of single daily (RH) and twice-daily episodes of insulin-induced hypoglycemia (2RH) on adrenal epinephrine release and production in normal rats. Control animals received saline injections under similar conditions (RS and 2RS, respectively). Following 3 days of treatment, we assessed the counterregulatory hormonal responses during a hypoglycemic clamp. Changes in adrenal TH gene expression were also analyzed. The counterregulatory responses, relative TH transcription and TH mRNA levels and Ser40-TH phosphorylation (marker for enzyme activation) were induced to a similar extent in RS, 2RS, and RH groups. In contrast, epinephrine and glucagon responses were attenuated in the 2RH group and this was associated with a limited elevation of adrenal TH mRNA, rapid inactivation of TH enzyme and no significant changes in TH protein. Our results suggest that novel posttranscriptional mechanisms controlling TH mRNA and activated TH enzyme turnover contribute to the impaired epinephrine responses and may provide new therapeutic targets to prevent HAAF.

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Cytisine: State of the art in pharmacological activities and pharmacokinetics

Wang,

Yang,

Huang

et al. 2024

Biomedicine & Pharmacotherapy

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Nicotinic receptor partial agonists alter catecholamine homeostasis and response to nicotine in PC12 cells

Cited by 5 publications

References 33 publications

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

Posttranscriptional regulation of adrenal TH gene expression contributes to the maladaptive responses triggered by insulin-induced recurrent hypoglycemia

Cytisine: State of the art in pharmacological activities and pharmacokinetics

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