Leaky catecholamine stores: undue waste or a stress response coping mechanism?

Turnover of catecholamines, representing the constant loss and replenishment of neurotransmitter by synthesis, is usually considered to be driven exclusively by catecholamine release. This is incorrect. An important contribution of intraneuronal metabolism of norepinephrine to turnover, and dependence of this on leakage of norepinephrine from vesicular stores, was originally proposed by Kopin in 1964. Several years later, Maas and colleagues concluded that at least 75% of norepinephrine turnover is due to intraneuronal metabolism without prior release at sympathetic nerve endings. More recently it was shown in the resting human heart that about 12% of norepinephrine turnover is due to extraneuronal uptake and metabolism or loss of the transmitter to the circulation, 15% is due to intraneuronal metabolism after reuptake, and 73% is due to intraneuronal metabolism of norepinephrine leaking from storage vesicles. Thus, contrary to usual depictions, vesicular stores of catecholamines do not exist in a static state simply waiting for exocytotic release. Rather, these stores exist in a highly dynamic equilibrium with the surrounding cytoplasm, with passive outward leakage of amines counterbalanced by inward active transport under the control of vesicular monoamine transporters. The large contribution of leakage to catecholamine turnover may seem inconsistent with cellular economy. In fact, this contribution provides an important mechanism for "gearing down" the requirement for increases in catecholamine synthesis to match increases in catecholamine release, and thereby provides sympathetic nerves with a capacity for a more extended range of sustainable release rates in response to stress than would otherwise be possible.