Attenuated PLD1 association and signalling at the H452Y polymorphic form of the 5-HT2A receptor

► Distinct PLC and PLD signalling pathways of the psychotropic 5-HT2AR were measured. ► H452Y variant 5-HT2AR, associated with CNS disorders, and wild-type were compared. ► H452Y mutation selectively disrupts PLD signalling over conventional PLC signalling. ► H452Y mutation reduces direct binding of PLD1 to the 5-HT2AR carboxy-terminal tail. ► 5-HT2AR residues 450-460 are implicated in PLD signalling and downstream responses.