Paul Smith

Contact

• workRoom CS 89c The University of Nottingham Medical School
  Queen's Medical Centre
  Nottingham
  NG7 2UH
  UK
• work0115 82 30135
• fax0115 82 30081
• paul.a.smith@nottingham.ac.uk

Expertise Summary

A rise in the concentration of intracellular of calcium ions is a key signal in the stimulus-secretion coupling of peptide hormones from endocrine cells and peptidergic neurons. This increase primarily occurs via calcium influx across the plasmamembrane through calcium selective ion channels that open in response to action potential electrical activity stimulated by secretagogues. Two peptide secretory systems particularly interest me: The secretion of insulin from the pancreatic b-cell, in which dysfunctional release underlies blood sugar disorders e.g. diabetes and obesity. Secondly, that of leptin secretion from adipocytes in which dysfunctional release is thought to be involved in eating disorders and obesity. Stimulus-secretion coupling is modulated by a wide variety of neurotransmitters and hormones. Although the mode of action of these molecules is diverse, the majority of these agents directly affect the calcium-dependent stimulus-secretion coupling pathway outlined above. Somatostatin is one such molecule that is well established to inhibit secretion. Its analogues are used for the treatment of hyperinsulineamia and are currently under trial for the recution of some forms of obesity. Another hormone that affects energy balance is growth hormone this stimulates leptin secretion. Therefore the receptors for somatostatin and growth hormone are important therapeutic targets. My current research is focused on the investigation of the molecular pharmacology of the actions of somatostatin and growth hormone on endocrine cells and their secretory function.

Research Interests

• Molecular pharmacology of somatostatin receptors: effects on cell metabolism and ion channel function
• The electrophysiology of adipocytes and the role of ion channels in their function.
• Regulation of the trafficking and expression of L-type Ca2+ channels in endocrine cells.
• Multi-electrode-array analysis of electrical behaviour in pancreatic b-cells.
• Real time recording of quantal peptide secretion from endocrine cells, identification of sequential and compound exoxytosis using amperometry, patch-clamp and mathematical techniques

Research Techniques/Expertise

• Electrophysiology of secretory-cells and neurons: sharp-electrode, patch-clamp (all configurations, inc. cell infusion, perforated patch and also single-channel kinetic analysis)
• Real-time measurement of secretion from single cells: capacitance method, amperometry (inc. multiple simultaneous measurement and also quantal analysis)
• Single cell microfluorimetry (Ca2+, RH123, NAD(P)H)
• Measurement of oxidative respiration: RH123, NAD(P)H, MTS assay, O2.
• Isolation and culture of pancreatic islets and b-cells from fish, rodent and human pancreas
• Cell proliferation assays
• Mathematical modelling and simulation (cell-signals, secretion, electrophysiology).

Course convenor for, and teacher on,:

B31A03 Physiology and Pharmacology 1 B31A11 Laboratory Studies in Physiology and Pharmacology B12305 Neuroscience Tutorial Module II B12366 Neuronal Signalling Taught course: Channelopathy

Research Summary

Electrophysiology, especially of secretory-cells and neurones: microelectrode, patch-clamp (all configurations inc. perforated-patch and single-channel analysis). Real-time measurement of… read more

Selected Publications

• DAUNT, M., DALE, O. and SMITH, P.A, 2006. Somatostatin inhibits oxidative respiration in pancreatic beta-cells. Endocrinology. 147(3), 1527-1535
• SMITH, P A, SELLERS, L A and HUMPHREY, P P, 2001. Somatostatin activates two types of inwardly rectifying K+ channels in MIN-6 cells. Journal of Physiology. 532(1), 127-142
• VIRSOLVY, A., SMITH, P., BERTRAND, G., GROS, L., HÉRON, L., SALAZAR, G., PUECH, R. and BATAILLE, D, 2002. Block of Ca(2+)-channels by alpha-endosulphine inhibits insulin release. British Journal of Pharmacology. 135(7), 1810-8
• SAGAR, D. R., SMITH, P. A., MILLNS, P. J., SMART, D., KENDALL, D. A. and CHAPMAN, V., 2004. TRPV1 and CB1 receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat European Journal of Neuroscience. 20(1), 175-184

• View all publications

Current Research

Electrophysiology, especially of secretory-cells and neurones: microelectrode, patch-clamp (all configurations inc. perforated-patch and single-channel analysis). Real-time measurement of neurotransmitter and peptide secretion from endocrine-cells andneurones: capacitance method, carbon-fibre amperometry (inc. quantal analysis). Microfluorimetry of cell-signals simultaneous with electrophysiology and secretion measurements. Measurement of oxidative respiration. Isolation of pancreatic isletsand beta-cells from fish, rodent and human pancreas; cell-lines. Mathematical modelling and simulation (cell-signalling, secretion, electrophysiology). Signal processing, statistics, data handling and analytical techniques.

Future Research

Molecular pharmacology and ionic mechanism of the sensitisation of nociceptive sensory neurones of the trigeminal ganglia by bradykinin and its suppression by somatostatin.Molecular pharmacology of the inhibition of L-type Ca2+-currents by somatostatinin

• WARD, DANIEL R, DEAR, FIONA M, WARD, IAN A, ANDERSON, SUSAN I, SPERGEL, DANIEL J, SMITH, PAUL A and EBLING, FRANCIS J P, 2009. Innervation of gonadotropin-releasing hormone neurons by peptidergic neurons conveying circadian or energy balance information in the mouse. PLoS ONE. 4, e5322
• SMITH, P.A., 2009. N-Type Ca^2^+-Channels in Murine Pancreatic beta -Cells Are Inhibited by an Exclusive Coupling with Somatostatin Receptor Subtype 1 ENDOCRINOLOGY -PHILADELPHIA PHIA-. VOL 150(NUMB 2), 741-748
• ATHANASIOU, ANDRIANI, SMITH, PAUL A, VAKILPOUR, SARA, KUMARAN, NETHIA M, TURNER, AMY E, BAGIOKOU, DIMITRA, LAYFIELD, ROBERT, RAY, DAVID E, WESTWELL, ANDREW D, ALEXANDER, STEPHEN P H and KENDALL, DAVID A, 2007. Vanilloid receptor agonists and antagonists are mitochondrial inhibitors: how vanilloids cause non-vanilloid receptor mediated cell death. Biochemical and Biophysical Research Communications. 354(1), 50-5
• ATHANASIOU, ANDRIANI, CLARKE, ANNA B, TURNER, AMY E, KUMARAN, NETHIA M, VAKILPOUR, SARA, SMITH, PAUL A, BAGIOKOU, DIMITRA, BRADSHAW, TRACEY D, WESTWELL, ANDREW D, FANG, LIN, LOBO, DILEEP N and CONSTANTIN, 2007. Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death. Biochemical and biophysical research communications. 364(1), 131-7
• DAUNT, M., DALE, O. and SMITH, P.A, 2006. Somatostatin inhibits oxidative respiration in pancreatic beta-cells. Endocrinology. 147(3), 1527-1535
• SAGAR, D. R., SMITH, P. A., MILLNS, P. J., SMART, D., KENDALL, D. A. and CHAPMAN, V., 2004. TRPV1 and CB1 receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat European Journal of Neuroscience. 20(1), 175-184
• VIRSOLVY, A., SMITH, P., BERTRAND, G., GROS, L., HÉRON, L., SALAZAR, G., PUECH, R. and BATAILLE, D, 2002. Block of Ca(2+)-channels by alpha-endosulphine inhibits insulin release. British Journal of Pharmacology. 135(7), 1810-8
• SMITH, P A, SELLERS, L A and HUMPHREY, P P, 2001. Somatostatin activates two types of inwardly rectifying K+ channels in MIN-6 cells. Journal of Physiology. 532(1), 127-142
• THOMAS, P and SMITH, P A, 2001. Tetrabutylammonium: a selective blocker of the somatostatin-activated hyperpolarizing current in mouse AtT-20 corticotrophs. Pflugers Archiv - European Journal of Physiology. 441(6), 816-23