Voltage-gated calcium channels in the Ca(v)2 channel class are regulators of synaptic transmission and are highly modified by transmitter inputs that activate synaptic G-protein-coupled receptors (GPCRs). A ubiquitous form of G-protein modulation involves an inhibition of mammalian Ca(v)2.1 and Ca(v)2.2 channels by Gbetagamma dimers that can be relieved by high-frequency trains of action potentials. Here, we address whether the ubiquitous and versatile form of G-protein regulation in mammals is also found in simpler invertebrate nervous systems. Remarkably, the invertebrate LCa(v)2 channel from the pond snail, Lymnaea stagnalis, does not bear any of the hallmarks of mammalian, voltage-dependent G-protein inhibition of Ca(v)2.2. Swapping either the I-II linker or N-terminus of Ca(v)2.2, which serve as key binding domains for G-protein inhibition, does not endow invertebrate LCa(v)2 channels with voltage-dependent G-protein modulatory capacity. Instead, in vitro expressed LCa(v)2 channels are inhibited slowly by the activation of cAMP, in a manner that depends on G-proteins but does not depend on Gbetagamma subunits. A similar G-protein and cAMP-dependent inhibition of nifedipine-insensitive LCa(v)2 currents is also consistent in native and identified Lymnaea VD4 neurons. The slower inhibition using a cellular messenger such as cAMP may meet the modulatory needs in invertebrates while an activity-dependent regulation, evolving in vertebrates, provides a more dynamic, fine-tuning of neurosecretion by regulating the influence of neurotransmitter inputs through presynaptic GPCRs.