Abstract
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 …
Highlights
It is well established that calcium is the trigger for fast action potentialevoked synaptic transmission [1]
The nifedipine-induced stimulatory effect on miniature excitatory postsynaptic currents (mEPSCs) frequency was not blocked by several strategies that interfere with calcium elevation including thapsigargin, a Ca2ϩ-ATPase inhibitor that depletes Ca2ϩ stores, chelation of [Ca2ϩ]i with 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetateacetoxymethyl ester (BAPTA-AM), or nonselective blockade of voltage-dependent calcium channels (VDCCs) with Cd2ϩ
Hirasawa and Pittman [12] are quite thorough and exclude the possibility that nifedipine blocks adenosine action leading to a disinhibition of miniature release and an apparent increase in mEPSC frequency
Summary
It is well established that calcium is the trigger for fast action potentialevoked synaptic transmission [1]. Regarding the mechanism by which nifedipine increases miniature synaptic activity, Hirasawa and Pittman [12] clearly show that it is completely independent of calcium-induced changes in basal release probability. To our knowledge there are a very few substances that can increase the frequency of miniature synaptic activity independently of changing [Ca2ϩ]i.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Proceedings of the National Academy of Sciences of the United States of America
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
