Sigma Proteins: Evolution of the Concept of Sigma Receptors

1. Front Matter

   Pages i-viii

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2. Introduction to Sigma Proteins: Evolution of the Concept of Sigma Receptors

   • Felix J. Kim

   Pages 1-11

3. Structural Insights into Sigma1 Function

   • Andrew Kruse

   Pages 13-25

4. 3D Homology Model of Sigma1 Receptor

   • Erik Laurini, Domenico Marson, Maurizio Fermeglia, Sabrina Pricl

   Pages 27-50

5. Medicinal Chemistry of σ1 Receptor Ligands: Pharmacophore Models, Synthesis, Structure Affinity Relationships, and Pharmacological Applications

   • Frauke Weber, Bernhard Wünsch

   Pages 51-79

6. Sigma-1 (σ1) Receptor in Memory and Neurodegenerative Diseases

   • Tangui Maurice, Nino Goguadze

   Pages 81-108

7. Sigma-1 Receptor and Neuronal Excitability

   • Saïd Kourrich

   Pages 109-130

8. Sigma-1 Receptor and Pain

   • Manuel Merlos, Luz Romero, Daniel Zamanillo, Carlos Plata-Salamán, José Miguel Vela

   Pages 131-161

9. Allosteric Modulation of Opioid G-Protein Coupled Receptors by Sigma1 Receptors

   • Gavril W. Pasternak

   Pages 163-175

10. A Role for Sigma Receptors in Stimulant Self-Administration and Addiction

    • Jonathan L. Katz, Takato Hiranita, Weimin C. Hong, Martin O. Job, Christopher R. McCurdy

    Pages 177-218

11. Sigma Receptors and Alcohol Use Disorders

    • Valentina Sabino, Pietro Cottone

    Pages 219-236

12. Sigma1 Pharmacology in the Context of Cancer

    • Felix J. Kim, Christina M. Maher

    Pages 237-308

13. Molecular Probes for Imaging the Sigma-2 Receptor: In Vitro and In Vivo Imaging Studies

    • Chenbo Zeng, Elizabeth S. McDonald, Robert H. Mach

    Pages 309-330

Two sigma receptor subtypes have been proposed, sigma1 and 2. Much of our understanding of this system is based on biochemical and pharmacological characterization of the cloned sigma1 receptor subtype (Sigma1). It has become clear that sigma receptors are not canonical receptors. Sigma1 is highly conserved among mammalian species, however, it does not share significant homology with any other mammalian protein. Although a range of structurally diverse small molecules bind Sigma1 with high affinity, and it has been associated with a broad range of signaling systems, Sigma1 itself has no known signaling or enzymatic activity. The evolution of this field over nearly four decades has more recently led to a fundamental shift in the concept of “sigma receptors” to what may more accurately and generally be called sigma proteins. Largely based on traditional pharmacologic approaches, the Sigma1 protein has been associated with a broad range of signaling systems, including G-protein coupled receptors, NMDA receptors, and ion channels. Sigma proteins have been linked to a range of physiological processes, including intracellular calcium signaling, neuroprotection, learning, memory, and cognition. Emerging genetic, clinical, and mechanism focused molecular pharmacology data demonstrate the involvement of proteins in a range of pathophysiologies and disorders including neurodegenerative disease, pain, addiction, psychomotor stimulant abuse, and cancer. However, an understanding of the physiological role of sigma proteins has remained elusive. Emerging data associate Sigma1 with chaperone-like activities or molecular scaffold functions. This book aims to provide an updated perspective on this rapidly evolving field undergoing changes in fundamental concepts of key importance to the discipline of pharmacology. It focusses on the reported roles of sigma proteins in pathophysiology and on emergent therapeutic initiatives.

• Chaperone
• Neurodegenerative disease
• Pain
• Pathophysiology
• Protein homeostasis
• Scaffold

• Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, USA

  Felix J. Kim

• Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, USA

  Gavril W. Pasternak

Felix J Kim PhD, Drexel University, College of Medicine, Pharmacology and Physiology, Philadelphia, USA
Gavril Pasternak MD Ph., Memorial Sloan-Kettering Cancer Center, Anne Burnett Tandy Chair in Neurology, Molec Pharmacology and Chemistry, New York, USA

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