Calcium-Independent Release of Neurotransmitter in the Retina: a ``Copernican'' Viewpoint Change Marco Piccolino*, Angela Pignatelli and Liramalala A. Rakotobe Dipartimento di Biologia dell'Universita Á di Ferrara, Sezione di Fisiologia Generale, Ferrara, Italy CONTENTS Abstract ............................................................................ 2 1. Introduction .......................................................................... 2 1.1. Preliminary considerations: Copernicus and Hodgkin±Huxley ........................... 2 1.2. A paradox: more Ca 2+ may enter into synaptic terminals when [Ca 2+ ] o is lowered ......... 3 1.3. Divalent cations and surface charges ................................................. 4 2. Surface charge theory .................................................................. 5 2.1. Outline of the theory and surface charge changes induced by extracellular ions ............. 5 2.2. Surface charge buering of divalent cations ........................................... 8 3. Surface potential and ionic channels ..................................................... 8 3.1. Surface charges and Ca 2+ channels .................................................. 9 4. Peculiarities of synaptic transmission from photoreceptors .................................. 12 4.1. Tonic transmitter release and ``misalignment'' of working range of photoreceptor potential and Ca 2+ current curve ............................................................ 12 4.2. Con¯icting results on the eects of divalent cations on synaptic transmission from vertebrate photoreceptors ................................................................... 15 4.2.1. The initial experiments: Ca 2+ -dependence of the transmission process ............... 15 4.2.2. Subsequent studies and the idea of a Ca 2+ -independent transmission................ 15 4.2.3. The importance of Mg 2+ ..................................................... 18 4.2.4. Surprising eects of transretinal currents ........................................ 19 4.2.5. The absence of Ca 2+ : is that the critical dierence? ............................... 20 5. New experiments ...................................................................... 20 5.1. Eects of low-Ca 2+ media on the synaptic transmission block induced by divalent cations . . . 20 5.2. Experiments with transretinal currents ............................................... 23 5.3. Dierence among divalent cations: ``unblockable'' and ``not-unblockable'' ions............. 25 5.4. Eects of divalent cations on photoreceptor Ca 2+ current............................... 25 5.5. Diculties with the surface charge hypothesis: the concentration of divalent cations in the extracellular medium .............................................................. 27 5.6. Lowering [Ca 2+ ] o in the absence of exogenous divalent cations: Mg 2+ makes the dierence . . 29 6. Conclusions .......................................................................... 31 6.1. Considerations on the insidious character of some scienti®c results ....................... 31 Progress in Retinal and Eye Research Vol. 18, No. 1, pp. 1 to 38, 1998 # 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 1350-9462/98/$19.00 + 0.00 PII: S1350-9462(98)00015-9 *Corresponding author: Dr Marco Piccolino, Dipartimento di Biologia dell'UniversitaÁ di Ferrara, Sezione di Fisiologia Generale, Ferrara, Via Borsari 46, 44100, Ferrara, Italy. Tel.: +39-532-291 470, fax: +39-532-207 143, e-mail: mbxpiccolino@- mailsrv.cnuce.cnr.it