Pre-synaptic sympathetic calcium channels, cyclic nucleotide-coupled phosphodiesterases and cardiac excitability

In sympathetic neurons innervating the heart, action potentials activate voltage-gated Ca²⁺ channels and evoke Ca²⁺ entry into presynaptic terminals triggering neurotransmitter release. Binding of transmitters to specific receptors stimulates signal transduction pathways that cause changes in cardiac function. The mechanisms contributing to presynaptic Ca²⁺ dynamics involve regulation of endogenous Ca²⁺ buffers, in particular the endoplasmic reticulum, mitochondria and cyclic nucleotide targeted pathways. The purpose of this review is to summarize and highlight recent findings about Ca²⁺ homeostasis in cardiac sympathetic neurons and how modulation of second messengers can drive neurotransmission and affect myocyte excitability in cardiovascular disease. Moreover, we discuss the underlying mechanism of abnormal intracellular Ca²⁺ homeostasis and signaling in these neurons, and speculate on the role of phosphodiesterases as a therapeutic target to restore normal autonomic transmission in disease states of overactivity.