ABSTRACT
Implications for Ca2þ Channels................................................... 462 17.2 Current Drug Discovery Approaches........................................................ 462
17.2.1 Overview....................................................................................... 462
17.2.2 Target Selection............................................................................ 462
17.2.3 Hit-Finding ................................................................................... 464
17.2.4 Hit to Lead.................................................................................... 464
17.2.5 Lead Optimization ........................................................................ 465
17.2.6 Summary....................................................................................... 465
17.3 Emerging Ca2þ Channel Targets .............................................................. 466 17.3.1 TRPV1 Channels .......................................................................... 466
17.3.2 N-Type Voltage-Operated Ca2þ Channels ................................. 467 17.4 Assays and Technologies for Ca2þ Channel Drug Discovery ................. 468
17.4.1 Cell Lines...................................................................................... 468
17.4.2 Radioligand Binding..................................................................... 469
17.4.3 Radiotracer Flux ........................................................................... 471
17.4.4 Optical Readouts — Intracellular Ca2þ Concentration and Membrane Potential............................................................... 472
17.4.5 Electrophysiology — Patch Clamp and
Oocyte Recording......................................................................... 476
17.5 Concluding Remarks ................................................................................. 479
Acknowledgments ................................................................................................ 479
Appendix............................................................................................................... 480
References............................................................................................................. 481
In all cell types Ca2þ influx through plasma membrane channels is of fundamental importance in both physiology and pathophysiology, e.g., contraction of muscle
cells, neurotransmitter release from nerve terminals, secretion by epithelial cells,
and leukocyte activation. Therefore, modulation of cell function by targeting these
channels represents a potentially effective approach for therapeutic intervention.
