Mind-altering miniature neurotransmitter release?

I t is well established that calcium is the trigger for fast action potentialevoked 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 M) (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 in the rate of miniature synaptic activity. Surprisingly, the effect of the drug has little to do with its action on the L-type VDCC, general calcium dynamics, or previously reported factors shown to affect mEPSC frequency such as nitric oxide (NO) and protein kinase cascades (Fig. 1). The authors imply that the drug may have a new potential site of action on the neurotransmitter release machinery itself or directly on the membrane fusion process. Although the exact mechanism is unclear, the results suggest that this commonly used therapeutic agent may have other mechanisms of action. Interestingly, the authors outline reports of CNS side effects apparently involving the DHP nifedipine (to a lesser extent than other DHPs) and imply that side effects could be attributed to modulation of miniature transmitter release. Electrophysiological studies reveal multiple types (T, L, N, P, Q, and R) of VDCCs based on molecular, physiological, and pharmacological criteria (13). DHPs are well known classical organic ligands that bind specifically and with high affinity to L-type VDCCs in cardiac, skeletal, and smooth muscle and are used as antag-