Figure 2. A schematic diagram of the possible mechanisms of presynaptic G_i/o coupled GPCR activation-induced LTD.

Activation of presynaptic G_i/o-coupled GPCRs results in the dissociation of the G_αi and G_βγ subunits from the receptor complex. G_βγ subunits directly and negatively couple to voltage-dependent Ca²⁺ channels (VDCCs) resulting in reduced Ca²⁺ entry into the presynaptic terminal. Reduced Ca²⁺ influx decreases vesicle fusion and neurotransmitter release probability. In addition, G_βγ may directly inhibit components of the vesicular release machinery (e.g. SNAP25). The G_αi subunits negatively couple to adenylyl cyclase (AC) resulting in decreased cAMP levels. A decrease in cAMP levels results in dampened PKA activity, which is associated with reduced functionality of RIM1α. RIM1α complexes with the vesicular proteins RAB3A and RAB3B to enhance neurotransmitter release. Therefore, reduced PKA activity directly or indirectly inhibits this complex’s ability to promote neurotransmission. In addition, Ca²⁺ entry through VDCCs or NMDARs activates the presynaptic kinases calmodulin and CaMKII and the protein phosphatase calcineurin. GPCR modulation of presynaptic Ca²⁺ levels likely influences the activity of these proteins, which subsequently alters neurotransmitter release. Although not directly modulated by presynaptic G_i/o GPCRs, nitric oxide (NO) signaling intersects with GPCR-mediated signaling to promote LTD. NO signaling results in PKG activation that influences release machinery function. Finally, at some synapses protein translation appears to be a necessary component of LTD maintenance. The mechanisms that engage the protein translation apparatus as well as the proteins that are expressed are currently unknown.