Emberhard et al. [11] found that the application of PI-specific phospholipase C into digitonin-permeabilized chromaffin cells decreased PI levels, and inhibited calcium-triggered exocytosis.

This exocytosis inhibition was preferential for an ATP-dependent stage, indicating PI function was required for secretion.

Studies utilizing PHPLCδ1 domain over-expression (acting as PI(4,5)P2 buffer or blocker) ,[14] PIPKIγ knockout in chromaffin cell [15] and in central nerve system,[16] PIPKIγ knockdown in beta cell lines ,[17] and over-expression of membrane-tethered inositol 5-phosphatase domain of synaptojanin 1 ,[18] all suggested vesicle (synaptic vesicle and LDCV) secretion were severely impaired after PI(4,5)P2 depletion or blockage.

PIP2 functions as an intermediate in the IP3/DAG pathway, which is initiated by ligands binding to G protein-coupled receptors activating the Gq alpha subunit.

[26][27] PtdIns(4,5)P2 has been shown to stabilize the active states of Class A G protein-coupled receptors (GPCRs) via direct binding, and enhance their selectivity toward certain G proteins.

This stabilizes GRK2 and also orients it in a way that allows for more efficient phosphorylation of the beta adrenergic receptor, a type of GPCR.