A novel cAMP-dependent pathway activates neuronal integrin function in retinal neurons.
Retinal neurons lose the ability to attach to and extend neurites on substrata of laminin-1 (LN-1) during late embryogenesis, in a time frame that corresponds to target innervation. Although this developmental loss correlates with a modest downregulation of integrin expression, we have shown previously that these neurons use the same laminin-binding integrins for outgrowth on other laminin isoforms to which responsivity has not been lost (Ivins et al., 1998), suggesting that integrin functional states may be a critical point of regulation. Consistent with this view, expression of an activated mutant of R-ras, an activator of integrin function, restores integrin-dependent outgrowth of late embryonic retinal neurons on LN-1 (Ivins et al., 2000). Because cyclic nucleotides have been implicated in the regulation of integrin function in non-neuronal cells, as well as in the regulation of growth cone responses to various axon growth inhibitors, we asked whether raising cAMP levels in late embryonic retinal neurons could activate neuronal integrin function and restore neurite outgrowth on LN-1. We find that, similar to R-ras expression, raising cAMP levels in these neurons promotes alpha6beta1 integrin-dependent neurite outgrowth. Surprisingly, these effects of cAMP are independent of protein kinase A and the EPAC (exchange protein directly activated by cAMP)/Rap pathway and suggest the existence of a novel cAMP-dependent mechanism.
Ivins
Jonathan K
JK
Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. jonathan.k.ivins@uth.tmc.edu
Parry
Melissa K
MK
Long
Dorothy A
DA
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020668:rap GTP-Binding Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D019012:Integrin beta1; D016023:Integrins; D007797:Laminin; C121346:laminin 1; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020668:rap GTP-Binding Proteins