Galanin inhibits tyrosine hydroxylase expression in midbrain dopaminergic neurons.
Galanin (GAL) inhibits midbrain dopamine (DA) activity in several experimental paradigms, yet the mechanism underlying this inhibition is unclear. We examined the effects of GAL on the expression of tyrosine hydroxylase (TH) in primary cultures of rat embryonic (E14) ventral mesencephalon (VM). One micromolar GAL had no effect on the number of TH-immunoreactive (ir) neurons in VM cultures. However, 1 micro m GAL reduced an approximately 100% increase in TH-ir neurons in 1 mm dibutyryl cAMP (dbcAMP)-treated cultures by approximately 50%. TH-ir neuron number in dbcAMP-treated VM cultures was dose-responsive to GAL and the GAL receptor antagonist M40 blocked GAL effects. Semi-quantitative RT-PCR and quantitative immunoblotting experiments revealed that GAL had no effect on TH mRNA levels in VM cultures but reduced TH protein. VM cultures expressed GALR1, GALR2, and GALR3 receptor mRNA. However, dbcAMP treatment resulted in a specific approximately 200% increase in GALR1 mRNA. GALR1 activity is linked to a pertussis toxin (PTX)-sensitive opening of G protein-gated K+ channels (GIRKs). GAL reduction of TH-ir neuron number in dbcAMP + GAL-treated cultures was sensitive to both PTX and tertiapin, a GIRK inhibitor. GAL inhibition of midbrain DA activity may involve a GALR1- mediated reduction of TH in midbrain dopaminergic neurons.
Counts
Scott E
SE
Department of Neurological Sciences and Pharmacology, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, USA.
McGuire
Susan O
SO
Sortwell
Caryl E
CE
Crawley
Jacqueline N
JN
Collier
Timothy J
TJ
Mufson
Elliott J
EJ
D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D019004:Galanin / Q000494:pharmacology*; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D001514:Bee Venoms; D012333:RNA, Messenger; D044088:Receptors, Galanin; D018013:Receptors, Neuropeptide; C029738:tertiapin; D003994:Bucladesine; D019004:Galanin; D014446:Tyrosine 3-Monooxygenase; D037342:Pertussis Toxin; D004298:Dopamine