The Role of Calcium in Neurotransmitter Release: Existing Models and New Approaches to Evaluate Possible Mechanisms

This chapter provides an overview of the role of calcium (Ca²⁺) in neurotransmitter release presenting existing models and new approaches to evaluate possible mechanisms. Neurotransmitter release is a complex process governed by Ca²⁺ ions. Many pathways leading to the elevation of intracellular calcium ions have been examined as possible pathways leading to secretion. The Ca²⁺ signal is composed of two phases, an initial fast and short phenomenon because of mobilization of [Ca²⁺] from intracellular stores and a secondary rise in [Ca²⁺]_cyt because of calcium influx via specific calcium channels as determined by Fura-2 and other chromophores. The relevance of [Ca²⁺]_i to neurotransmitter release is not simple. In some systems, such as PC-12 cells, the fast rise in [Ca²⁺]_i after stimulation with bradykinin is identical in the presence or absence of [Ca²⁺]_ex. Nevertheless, release occurs only in the presence of [Ca²⁺]_ex. Therefore, it should be taken into account that the measurements of [Ca²⁺]_i by Fura-2 or other Ca²⁺-sensitive dyes are limited in detection of [Ca²⁺]_i changes at close proximity to the membrane. As the opening of Ca²⁺ channels relevant to release is likely to occur at the membrane, the resolution of [Ca²⁺]_i determination may not truly reflect neurotransmitter release. The new approaches using imaging techniques with various fluorescent dyes allow determination of the magnitude, duration, and the precise distribution of Ca²⁺ transients in the cell. The emerging technique of patch clamping and recording from single cells is advances toward the understanding of the mechanism of neurotransmitter release.