Ryanodine receptors (RyRs) are Ca 2+ release channels located in the endoplasmic reticulum membrane. Presynaptic RyRs play important roles in neurotransmitter release and synaptic plasticity. Recent studies suggest that the proper function of presynaptic RyRs relies on several regulatory proteins, including aryl hydrocarbon receptor-interacting protein, calstabins, and presenilins. Dysfunctions of these regulatory proteins can greatly impact neurotransmitter release and synaptic plasticity by altering the function or expression of RyRs. This chapter aims to describe the interaction between these proteins and RyRs, elucidating their crucial role in regulating synaptic function.