title: Regulation of multiple tip formation by caffeine in cellular slime molds.
abstract: BACKGROUND
  The multicellular slug in Dictyostelium has a single tip that acts as an organising centre patterning the rest of the slug. High adenosine levels at the tip are believed to be responsible for this tip dominance and the adenosine antagonist, caffeine overrides this dominance promoting multiple tip formation.
  
  
  RESULTS
  Caffeine induced multiple tip effect is conserved in all the Dictyostelids tested. Two key components of cAMP relay namely, cAMP phosphodiesterase (Pde4) and adenyl cyclase-A (AcaA) levels get reduced during secondary tip formation in Dictyostelium discoideum. Pharmacological inhibition of cAMP phosphodiesterase also resulted in multiple tips. Caffeine reduces cAMP levels by 16.4, 2.34, 4.71 and 6.30 folds, respectively in D. discoideum, D. aureostipes, D. minutum and Polysphondylium pallidum. We propose that altered cAMP levels, perturbed cAMP gradient and impaired signalling may be the critical factors for the origin of multiple tips in other Dictyostelids as well. In the presence of caffeine, slug cell movement gets impaired and restricted. The cell type specific markers, ecmA (prestalk) and pspA (prespore) cells are not equally contributing during additional tip formation. During additional tip emergence, prespore cells transdifferentiate to compensate the loss of prestalk cells.
  
  
  CONCLUSIONS
  Caffeine decreases adenyl cyclase-A (AcaA) levels and as a consequence low cAMP is synthesised altering the gradient. Further if cAMP phosphodiesterase (Pde4) levels go down in the presence of caffeine, the cAMP gradient breaks down. When there is no cAMP gradient, directional movement is inhibited and might favour re-differentiation of prespore to prestalk cells.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology-Madras, Chennai 600036, India.
authors.forename: Pundrik
authors.initials: P
authors.lastname: Jaiswal
authors.forename: Shashi Prakash
authors.initials: SP
authors.lastname: Singh
authors.forename: Prasad
authors.initials: P
authors.lastname: Aiyar
authors.forename: Rakhil
authors.initials: R
authors.lastname: Akkali
authors.forename: Ramamurthy
authors.initials: R
authors.lastname: Baskar
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D054338:Cell Transdifferentiation; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism; D004023:Dictyostelium / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D015870:Gene Expression; D007700:Kinetics; D007769:Lactams / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002630:Chemotactic Factors; D004151:Dipeptides; D007769:Lactams; D058988:Phosphodiesterase 4 Inhibitors; D015800:Protozoan Proteins; D002110:Caffeine; C057791:glorin; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015056:1-Methyl-3-isobutylxanthine