The clone SH-SY5Y derived from human sympathetic ganglia, 1, extends neurites, 2 expresses L- and N-type voltage sensitive calcium channels, 3, contains two types of vesicles a) large dense cored vesicles (LDCV) which store noradrenaline (NA) and NPY and b) smaller electron-lucent vesicles, and 4, exhibits depolarisation-evoked calcium-dependent release of NA. Thus this cell line expresses several properties of mature, sympathetic neurones even when cultured in the absence of NGF, retinoic acid or the low concentrations of phorbol esters frequently used to induce neuronal differentiation in this call line. SH-SY5Y cells also express muscarinic (M₃), bradykinin (B₂) and, in cells transfected with rat AT_1A cDNA, angiotensin II receptors. These receptors are coupled to the release of Ca²⁺ from intracellular stores and following activation of protein kinase C the release of NA. This review focuses on two aspects of our current studies which are directed towards understanding the molecular mechanism by which receptors and second messengers regulate NA release. 1. Activation of protein kiase C-α (Pkc-α) enhances depolarisation and receptor-evoked NA release; and 2. Activation of muscarinic (M₃), bradykinin (B₂), NPY (Y₂) and angiotensin II (AT_1A) receptors inhibits Ca²⁺ channel activity and, in the case of muscarinic (M₁) receptors, inhibits depolarisation-evoked release of NA. 1. Our most recent studies suggest that activation of PKC-α leads to the accumulation of LDCVs at the plasma membrane. These observations are discussed in terms of a mechanism by which phosphorylation of the PKC substrate MARCKS results in the partial disassembly of the F-actin cytoskeleton which forms a sub-plasmalemmal barrier to exocytosis and hence the movement of LDCVs to release sites on the plasma membrane. 2. Our studies on the effect of receptor activation fall into two main groups. A. Rapid inhibition of voltage sensitive Ca²⁺ channels (usually N-type) by M₃ and NPY (Y₂) receptors by a pertussis toxin sensitive mechanism. This inhibition is most likely due to a membrane delimited action mediated via G_o. B. A slower inhibition of both L- and N-type Ca²⁺ channels by pertussis toxin insensitive mechanism. This effect has been most intensively studies for activation of M₁ receptors and leads to the inhibition of depolarisation-evoked NA release. This effect which is attenuated by activation of PKC is dependent on the release of Ca²⁺ from a small intracellular store. This review discusses our work in relation to current understanding in other secretory cell lines as well as acutely isolated sympathetic neurones.