1. Significance
There are some controversies in the field that the authors want to address, and the authors claim to have provided “a unifying explanation for seemingly conflicting data and emphasize the importance of the Ca2+-dependent phospholipid association in Doc2b-mediated secretory regulation”:
1) The gain- or loss-of-function debate of the Doc2b mutant proteins (Doc2bDN and Doc2b6A were reported differently in previous studies). The authors suggest that they have reconciled the previous studies by showing DN and 6A mutants do not have different gain- or loss-of-function pattern but show similar behavior: increased activity (gain-of-function) at rest but impaired activity at high [Ca2+] (loss-of-function) during neuronal activity.
2) Whether the Doc2b proteins function as Ca2+ sensors. The authors believe Doc2b functions as a Ca2+ sensor and argue that “the strict correlation between plasma membrane association and spontaneous release frequency supports a direct role as a Ca2+ sensor. In addition, a Ca2+-dependent function in synaptic recovery is also supported by the data”.