N termini of apPDE4 isoforms are responsible for targeting the isoforms to different cellular membranes.
Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the cytoplasm, plasma membrane, and both plasma membrane and presynaptic terminals, respectively. The N-terminal 20 amino acids of the long form of apPDE4 were involved in presynaptic terminal targeting by binding to several lipids. In addition, the N terminus of the short form of apPDE4 bound to several lipids including phosphoinositols, thereby targeting the plasma membrane. Overexpression of the long and the short forms, but not the supershort form attenuated 5-HT-induced membrane hyperexcitability. Finally, the knockdown of apPDE4s in sensory neurons impaired both short-term and long-term facilitation. Thus, these results suggest that apPDE4s can participate in the regulation of cAMP signaling through specific subcellular localization by means of lipid binding activities.
Jang
Deok-Jin
DJ
National Creative Research Initiative Center for Memory, Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanak-gu, Seoul, Korea.
Park
Soo-Won
SW
Lee
Jin-A
JA
Lee
Changhoon
C
Chae
Yeon-Su
YS
Park
Hyungju
H
Kim
Min-Jeong
MJ
Choi
Sun-Lim
SL
Lee
Nuribalhae
N
Kim
Hyoung
H
Kaang
Bong-Kiun
BK
D000595:Amino Acid Sequence; D000818:Animals; D001048:Aplysia; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D017952:Ganglia, Invertebrate / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008563:Membrane Lipids / Q000378:metabolism; D008564:Membrane Potentials / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D017729:Presynaptic Terminals / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D017434:Protein Structure, Tertiary; D034622:RNA Interference / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection / Q000379:methods
D008563:Membrane Lipids; D020033:Protein Isoforms; D016708:Synaptophysin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012701:Serotonin; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003545:Cysteine