Mind-altering miniature neurotransmitter release?

It is well established that calcium is the trigger for fast action potential-evoked synaptic transmission (1). After elevation of intracellular calcium ([Ca2+]i) by action potential-mediated opening of voltage-dependent calcium channels (VDCCs), a low resting rate of neurotransmitter release of 0.01–0.03 vesicles per sec is elevated significantly to ≈20 per sec (2–4). Transmitter release occurring independently of action potential-mediated changes in [Ca2+]i is termed “miniature release” and involves the stochastic release of individual vesicles (quanta). The quantal nature of miniature activity has been used to elucidate basic functional parameters of central nervous system (CNS) and neuromuscular synapses (5). Although miniature transmission can occur at basal [Ca2+]i levels (≈80 nM), its frequency is greatly stimulated by even modest [Ca2+]i elevation (<1 μM) (6). Miniature release has been proposed recently to have a role in maintaining the function of developing synapses during periods without action potential-evoked synaptic activity (refs. 7 and 8, but also see ref. 9) and is regulated in parallel to evoked release (10). In addition to being the trigger for fast chemical synaptic transmission, calcium is also required for coupling nerve-induced excitation to cardiac and smooth muscle contraction (11). As a treatment for hypertension and angina agents that interfere with calcium entry such as dihydropyridine (DHP), VDCC blockers are commonly used. Drugs with core 1,4-DHP structures potently block the L-type VDCC, which is required for muscle contraction. In the article by Hirasawa and Pittman (12) in this issue of PNAS, a paradoxical effect of the DHP nifedipine was found on miniature excitatory postsynaptic currents (mEPSCs) recorded from magnocellular neurons of the supraoptic nucleus of the hypothalamus. Specifically, nifedipine but not close chemical cousins such as nimodipine or nitrendipine potentially induces up to a 15-fold increase …