Voltage-gated calcium (Ca(2+)) channels initiate release of neurotransmitters at synapses, and regulation of presynaptic Ca(2+) channels has a powerful influence on synaptic strength. Presynaptic Ca(2+) channels form a large signaling complex, which targets synaptic vesicles to Ca(2+) channels for efficient release and mediates Ca(2+) channel regulation. Presynaptic plasticity regulates synaptic function on the timescale of milliseconds to minutes in response to neurotransmitters and the frequency of action potentials. This article reviews the regulation of presynaptic Ca(2+) channels by effectors and regulators of Ca(2+) signaling and describes the emerging evidence for a critical role of Ca(2+) channel regulation in control of neurotransmission and in presynaptic plasticity. Failure of function and regulation of presynaptic Ca(2+) channels leads to migraine, ataxia, and potentially other forms of neurological disease. We propose that presynaptic Ca(2+) channels serve as the regulatory node in a dynamic, multilayered signaling network that exerts short-term control of neurotransmission in response to synaptic activity.

Short-term synaptic plasticity shapes the postsynaptic response to bursts of impulses and is crucial for encoding information in neurons, but the molecular mechanisms are unknown. Here we show that activity-dependent modulation of presynaptic Ca(V)2.1 channels mediated by neuronal Ca(2+) sensor proteins (CaS) induces synaptic plasticity in cultured superior cervical ganglion (SCG) neurons. A mutation of the IQ-like motif in the C terminus that blocks Ca(2+)/CaS-dependent facilitation of the P/Q-type Ca(2+) current markedly reduces facilitation of synaptic transmission. Deletion of the nearby calmodulin-binding domain, which inhibits CaS-dependent inactivation, substantially reduces depression of synaptic transmission. These results demonstrate that residual Ca(2+) in presynaptic terminals can act through CaS-dependent regulation of Ca(V)2.1 channels to induce short-term synaptic facilitation and rapid synaptic depression. Activity-dependent regulation of presynaptic Ca(V)2.1 channels by CaS proteins may therefore be a primary determinant of short-term synaptic plasticity and information-processing in the nervous system.

CaV2.1 channels conduct P/Q-type Ca2+currents that are modulated by calmodulin (CaM) and the structurally related Ca2+-binding protein 1 (CaBP1). Visinin-like protein-2 (VILIP-2) is a CaM-related Ca2+-binding protein expressed in the neocortex and hippocampus. Coexpression of CaV2.1 and VILIP-2 in tsA-201 cells resulted in Ca2+channel modulation distinct from CaM and CaBP1. CaV2.1 channels with β2asubunits undergo Ca2+-dependent facilitation and inactivation attributable to association of endogenous Ca2+/CaM. VILIP-2 coexpression does not alter facilitation measured in paired-pulse experiments but slows the rate of inactivation to that seen without Ca2+/CaM binding and reduces inactivation of Ca2+currents during trains of repetitive depolarizations. CaV2.1 channels with β1bsubunits have rapid voltage-dependent inactivation, and VILIP-2 has no effect on the rate of inactivation or facilitation of the Ca2+current. In contrast, when Ba2+replaces Ca2+as the charge carrier, VILIP-2 slows inactivation. The effects of VILIP-2 are prevented by deletion of the CaM-binding domain (CBD) in the C terminus of CaV2.1 channels. However, both the CBD and an upstream IQ-like domain must be deleted to prevent VILIP-2 binding. Our results indicate that VILIP-2 binds to the CBD and IQ-like domains of CaV2.1 channels like CaM but slows inactivation, which enhances facilitation of CaV2.1 channels during extended trains of stimuli. Comparison of VILIP-2 effects with those of CaBP1 indicates striking differences in modulation of both facilitation and inactivation. Differential regulation of CaV2.1 channels by CaM, VILIP-2, CaBP1, and other neurospecific Ca2+-binding proteins is a potentially important determinant of Ca2+entry in neurotransmission.

Survival in small populations (e.g., Sierra Nevada bighorn sheep or Sierra bighorn [Ovis canadensis sierrae]) is often highly variable. External selective pressures vary in the degree to which they regulate survival by sex and age class. Understanding the important factors and risks for different demographic classes helps managers design strategies that enhance the recovery of endangered species, including Sierra bighorn. Our goal was to determine what population‐level factors (e.g., climate, habitat, population size, predation) affect survival and whether there are interactions between these factors by age and sex, and then apply our findings to recovery strategies. To this end, we conducted a known‐fate survival analysis for female and male Sierra bighorn with data collected over 12 years, and used model selection to evaluate models with spatial, environmental, and other population‐level factors hypothesized to be related to survival. Survival of adult Sierra bighorn declined continuously with age for both sexes; survival was generally higher for females than males, and there were no interactions between age and any environmental or population‐level factors. The top model for both sexes included the date of peak value of normalized difference vegetation index (NDVI) from the previous summer; NDVI had a similar positive relationship with survival for both sexes, which indicates that the later the growing season persists into the summer, the better survival the subsequent year. For females, survival also was negatively related to an index of abundance for mountain lions (Puma concolor), whereas the relationship was less apparent for males. Instead, top models for males indicated elevated survival during warm wet years, but years with late peaks in NDVI the previous year ameliorated the effect of a cold, dry winter. Finally, competitive models for males and females included a variable representing avalanche risk, indicating reduced survival in areas with increased avalanche risk. From a recovery management perspective, the lack of any interaction between age and other covariates suggests that although we may still select younger female Sierra bighorn for translocations (an essential recovery action) because they have higher reproductive value than old females, there were no additional negative synergies between age and other factors to consider. All variables are of value in guiding expectations for newly established populations and established source populations and some may help fine tune the selection of translocation areas. In addition, including predation, weather covariates, and catastrophic effects, such as avalanche risk, in projection models is important for realistic estimation of the time required to meet recovery goals and predicting population trajectories under likely climate change scenarios. Our approach is generalizable to other systems; we demonstrated how survival analyses can inform endangered species recovery management by indicating ideal areas for translocations and provided realist...

2ϩ -independent manner. Block of myristoylation abolished these effects, leaving regulation that is similar to endogenous CaM. CaBP1/G2A binds to Ca V 2.1 with reduced stability, but in situ protein cross-linking and immunocytochemical studies revealed that it binds Ca V 2.1 in situ and is localized to the plasma membrane by coexpression with Ca V 2.1, indicating that it binds effectively in intact cells. In contrast to CaBP1, coexpression of VILIP-2 slows inactivation in a Ca 2ϩ -independent manner, but this effect also requires myristoylation. These results suggest a model in which nonmyristoylated CaBP1 and VILIP-2 bind to Ca V 2.1 channels and regulate them like CaM, whereas myristoylation allows differential, Ca 2ϩ -independent regulation by the inactive EF-hands of CaBP1 and VILIP-2, which differ in their positions in the protein structure. Differential, myristoylation-dependent regulation of presynaptic Ca 2ϩ channels by nCaBPs may provide a flexible mechanism for diverse forms of short-term synaptic plasticity.