Figure 4.

Diagram showing molecular mechanisms of presynaptic CaMKII and BK channel functions. Presynaptic CaMKII may modulate neurotransmitter release through several possible mechanisms. First, CaMKII may promote synaptic vesicle translocation from the reserve pool to the readily releasable pool by phosphorylating synapsin I (SYN). Dephospho-synapsin I binds to synaptic vesicles (SVs) and keeps SVs in the reserve pool by associating with actin in the cytoskeleton whereas phosphor-synapsin I dissociates from actin and SVs, allowing SVs to translocate to the readily releasable pool. Second, CaMKII may increase Ca²⁺ entry by decelerating Ca_V2.1 (P/Q-type) channel inactivation. This effect of CaMKII is independent of its catalytic activity. Third, CaMKII may phosphorylate ryanodine receptors (RYR) to enhance Ca²⁺ release from the endoplasmic reticulum (ER). Fourth, CaMKII may downregulate neurotransmitter release by phosphorylating and activating the BK channel. Several other presynaptic proteins, including synaptotagmin (syt) and SNAREs, are also phosphorylated by CaMKII in vitro; however, the physiological significance is unclear. Presynaptic BK channel is activated by membrane depolarization and Ca²⁺ entry through colocalized voltage-sensitive Ca²⁺ channels (e. g. the P/Q-type channel). The BK channel downregulates neurotransmitter release by shortening the duration of action potentials that allow Ca²⁺ entry through voltage-sensitive Ca²⁺ channels. For clarity, CaMKII, syt, and SNAREs are depicted as stand-alone proteins although they normally associate with SVs or the plasma membrane.