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Our previous genetic analysis of synaptic mechanisms in Drosophila identified a temperature-sensitive Paralytic mutant of the voltage-gated calcium channel [alpha]1 subunit gene, cacophony (cac). Electrophysiological studies in this mutant, designated [cac.sup.TS2], indicated cac encodes a primary calcium channel [alpha]1 subunit functioning in neurotransmitter release. To further examine the functions and interactions of cac-encoded calcium channels, a genetic screen was performed to isolate new mutations that modify the [cac.sup.TS2] paralytic phenotype. The screen recovered 10 mutations that enhance or suppress [cac.sup.TS2], including second-site mutations in cac (intragenic modifiers) as well as mutations mapping to other genes (extragenic modifiers). Here we report molecular characterization of three intragenic modifiers and examine the consequences of these mutations for temperature-sensitive behavior, synaptic function, and processing of cac pre-mRNAs. These mutations may further define the structural basis of calcium channel [alpha]1 subunit function in neurotransmitter release.