Calcium 'leak' through somatic L-type channels has multiple deleterious effects on regulated transmitter release from...

Using an identified synapse in the nervous system of the mollusc Hermissenda, the influence of somatic calcium accumulation on regulated synaptic transmission was investigated. Hair cells in Hermissenda project onto postsynaptic B photoreceptors where they mediate inhibitory postsynaptic potentials (IPSPs). Intracellular recordings in combination with bath perfusion of calcium channel modulators indicated that L-type channels were present on the hair cell soma but not on the terminal branches. In contrast, P/Q and an unidentified channel type (similar to N-type channels) contributed additively to transmitter release from the hair cell. Antibodies raised against rat brain channel proteins detected L- (alpha1(C)) and P/Q-type (alpha1(A)) channels in lysates of the Hermissenda nervous system, indicating a homology between the Hermissenda channels and their mammalian counterparts. To mimic somatic calcium channel 'leak', hair cells were exposed to the L-type channel agonist +/-BAY K 8644. Exposure to +/-BAY K 8644 resulted in a rapid (<2 min) increase (40%) in the amplitude of the spike after-hyperpolarization in the hair cell, and was associated with a reduction in evoked firing frequency. This reduction in rate of discharge induced a proportional decrease in the amplitude of compound IPSPs recorded in the postsynaptic B photoreceptors. From Fura-2 emissions we determined that +/-BAY K 8644 induced a rapid (<2 min) and persistent increase (70%) in somatic calcium concentration, followed by a slower elevation of calcium in the medial axon (>30 min) and subsequently in the terminal branches (>40 min), suggesting that excessive somatic calcium had diffused or induced a propagation along the axon. Corresponding with a 56% rise in terminal calcium (50-60 min post agonist), postsynaptic potentials declined to 70% of baseline amplitude. These results suggest that prolonged somatic L-channel 'leak' can interfere with regulated transmitter release, both by reducing the rate of presynaptic discharge and by promoting terminal calcium accumulation that may oppose transmitter release. Such effect may have implications for the age-related learning deficits that often accompany somatic calcium 'leak'.