Medical Pharmacology Commons^™

A Transposon In Comt Generates Mrna Variants And Causes Widespread Expression And Behavioral Differences Among Mice, Zhengsheng Li, Megan K. Mulligan, Xusheng Wang, Michael F. Miles, Lu Lu, Robert W. Williams

Pharmacology and Toxicology Publications

Background

Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits.

Methodology/Principal Findings

We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 …

Synchronization Of Pancreatic Islet Oscillations By Intrapancreatic Ganglia: A Modeling Study, B. Fendler, M. Zhang, L. Satin, R. Bertram

Pharmacology and Toxicology Publications

Abstract

Plasma insulin measurements from mice, rats, dogs, and humans indicate that insulin levels are oscillatory, reflecting pulsatile insulin secretion from individual islets. An unanswered question, however, is how the activity of a population of islets is coordinated to yield coherent oscillations in plasma insulin. Here, using mathematical modeling, we investigate the feasibility of a potential islet synchronization mechanism, cholinergic signaling. This hypothesis is based on well-established experimental evidence demonstrating intrapancreatic parasympathetic (cholinergic) ganglia and recent in vitro evidence that a brief application of a muscarinic agonist can transiently synchronize islets. We demonstrate using mathematical modeling that periodic pulses of …

Morphine Exacerbates Hiv-1 Tat-Induced Cytokine Production In Astrocytes Through Convergent Effects On [Ca2+]I, Nf-Κb Trafficking And Transcription, Nazira El-Hage, Annadora J. Bruce-Keller, Tatiana Yakovleva, Igor Bazov, Georgy Bakalkin, Pamela E. Knapp, Kurt F. Hauser

Pharmacology and Toxicology Publications

Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-κB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-κB inhibitor parthenolide provided evidence that Tat±morphine-induced …

Long Lasting Synchronization Of Calcium Oscillations By Cholinergic Stimulation In Isolated Pancreatic Islets, Min Zhang, Bernard Fendler, Bradford Peercy, Pranay Goel, Richard Bertram, Arthur Sherman, Leslie Satin

Pharmacology and Toxicology Publications

Abstract

Individual mouse pancreatic islets exhibit oscillations in [Ca²⁺]_i and insulin secretion in response to glucose in vitro, but how the oscillations of a million islets are coordinated within the human pancreas in vivo is unclear. Islet to islet synchronization is necessary, however, for the pancreas to produce regular pulses of insulin. To determine whether neurohormone release within the pancreas might play a role in coordinating islet activity, [Ca²⁺]_i changes in 4–6 isolated mouse islets were simultaneously monitored before and after a transient pulse of a putative synchronizing agent. The degree of synchronicity was …

Gap Junction Coupling And Calcium Waves In The Pancreatic Islet, Richard K.P. Benninger, Min Zhang, W. Steven Head, Leslie S. Satin, David W. Piston

Pharmacology and Toxicology Publications

Abstract

The pancreatic islet is a highly coupled, multicellular system that exhibits complex spatiotemporal electrical activity in response to elevated glucose levels. The emergent properties of islets, which differ from those arising in isolated islet cells, are believed to arise in part by gap junctional coupling, but the mechanisms through which this coupling occurs are poorly understood. To uncover these mechanisms, we have used both high-speed imaging and theoretical modeling of the electrical activity in pancreatic islets under a reduction in the gap junction mediated electrical coupling. Utilizing islets from a gap junction protein connexin 36 knockout mouse model together …

Interaction Of Glycolysis And Mitochondrial Respiration In Metabolic Oscillations Of Pancreatic Islets, Richard Bertram, Leslie S. Satin, Morten Gram Pedersen, Dan S. Luciani, Arthur Sherman

Pharmacology and Toxicology Publications

Abstract

Insulin secretion from pancreatic β-cells is oscillatory, with a typical period of 2–7 min, reflecting oscillations in membrane potential and the cytosolic Ca²⁺ concentration. Our central hypothesis is that the slow 2–7 min oscillations are due to glycolytic oscillations, whereas faster oscillations that are superimposed are due to Ca²⁺ feedback onto metabolism or ion channels. We extend a previous mathematical model based on this hypothesis to include a more detailed description of mitochondrial metabolism. We demonstrate that this model can account for typical oscillatory patterns of membrane potential and Ca²⁺ concentration in islets. It also …

Calcium And Glycolysis Mediate Multiple Bursting Modes In Pancreatic Islets, Richard Bertram, Leslie S. Satin, Min Zhang, Paul Smolen, Arthur Sherman

Pharmacology and Toxicology Publications

Abstract

Pancreatic islets of Langerhans produce bursts of electrical activity when exposed to stimulatory glucose levels. These bursts often have a regular repeating pattern, with a period of 10–60 s. In some cases, however, the bursts are episodic, clustered into bursts of bursts, which we call compound bursting. Consistent with this are recordings of free Ca²⁺ concentration, oxygen consumption, mitochondrial membrane potential, and intraislet glucose levels that exhibit very slow oscillations, with faster oscillations superimposed. We describe a new mathematical model of the pancreatic β-cell that can account for these multimodal patterns. The model includes the feedback of …

The Ca2+ Dynamics Of Isolated Mouse Β-Cells And Islets: Implications For Mathematical Models, Min Zhang, Paula Goforth, Richard Bertram, Arthur Sherman, Leslie S. Satin

Pharmacology and Toxicology Publications

ABSTRACT

[Ca²⁺]_i and electrical activity were compared in isolated β-cells and islets using standard techniques. In islets, raising glucose caused a decrease in [Ca²⁺]_i followed by a plateau and then fast (2–3 min⁻¹), slow (0.2–0.8 min⁻¹), or a mixture of fast and slow [Ca²⁺]_i oscillations. In β-cells, glucose transiently decreased and then increased [Ca²⁺]_i, but no islet-like oscillations occurred. Simultaneous recordings of [Ca²⁺]_i and electrical activity suggested that differences in [Ca²⁺]_i signaling are due to …

The Phantom Burster Model For Pancreatic Β-Cells, Richard Bertram, Joseph Previte, Arthur Sherman, Tracie A. Kinard, Leslie S. Satin

Pharmacology and Toxicology Publications

Abstract

Pancreatic β-cells exhibit bursting oscillations with a wide range of periods. Whereas periods in isolated cells are generally either a few seconds or a few minutes, in intact islets of Langerhans they are intermediate (10–60 s). We develop a mathematical model for β-cell electrical activity capable of generating this wide range of bursting oscillations. Unlike previous models, bursting is driven by the interaction of two slow processes, one with a relatively small time constant (1–5 s) and the other with a much larger time constant (1–2 min). Bursting on the intermediate time scale is generated without need …

Modulation Of The Bursting Properties Of Single Mouse Pancreatic Β-Cells By Artificial Conductances, T.A. Kinard, G. De Vries, A. Sherman, L. S. Satin

Pharmacology and Toxicology Publications

Abstract

Glucose triggers bursting activity in pancreatic islets, which mediates the Ca²⁺ uptake that triggers insulin secretion. Aside from the channel mechanism responsible for bursting, which remains unsettled, it is not clear whether bursting is an endogenous property of individual β-cells or requires an electrically coupled islet. While many workers report stochastic firing or quasibursting in single cells, a few reports describe single-cell bursts much longer (minutes) than those of islets (15–60 s). We studied the behavior of single cells systematically to help resolve this issue. Perforated patch recordings were made from single mouseβ-cells or hamster …

Inactivation Of Hit Cell Ca2+ Current By A Simulated Burst Of Ca2+ Action Potentials, L. S. Satin, S. J. Tavalin, P. D. Smolen

Pharmacology and Toxicology Publications

ABSTRACT A novel voltage-clamp protocol was developed to test whether slow inactivation of Ca2+ current occurs during bursting in insulin-secreting cells. Single insulin-secreting HIT cells were patch-clamped and their Ca2+ currents were isolated pharmacologically. A computed ,3-cell burst was used as a voltage-clamp command and the net Ca2+ current elicited was determined as a cadmium difference current. Ca2+ current rapidly activated during the computed plateau and spike depolarizations and then slowly decayed. Integration of this Ca2+ current yielded an estimate of total Ca influx. To further analyze Ca2+ current inactivation during a burst, repetitive test pulses to + 10 mV …