Modulation of K+ and Ca2+ currents in cultured neurons by an angiotensin II type 1a receptor peptide.
Angiotensin II (ANG II) inhibits delayed rectifier K+ current (IK) and stimulates total Ca2+ current (ICa) in neurons cocultured from newborn rat hypothalamus and brain stem, effects mediated via ANG II type 1 (AT1) receptors. Here, we identify potential G protein activator regions of the AT1 receptor responsible for initiating the intracellular changes that lead to alterations in these currents. Intracellular application into cultured neurons of a peptide corresponding to the third cytoplasmic loop of the AT1 receptor (AT1a/i3) mimicked the actions of ANG II on IK and ICa, whereas application of a peptide corresponding to the second cytoplasmic loop (AT1a/i2) did not alter these currents. This modulation of IK and ICa by AT1a/i3 involves intracellular messengers (G alpha q, protein kinase C, and intracellular Ca2+) that are identical to those involved in the modulation of IK and ICa following ANG II activation of AT1 receptors. These data provide functional evidence for a role of the third cytoplasmic loop of the AT1 receptor in G protein coupling and subsequent modulation of ion channel effectors.
Zhu
M
M
Department of Physiology, College of Medicine, University of Florida, Gainesville 32610, USA.
Neubig
R R
RR
Wade
S M
SM
Posner
P
P
Gelband
C H
CH
Sumners
C
C
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D008969:Molecular Sequence Data; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000737:chemistry / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology; D015290:Second Messenger Systems; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009281:Naphthalenes; D010446:Peptide Fragments; D015221:Potassium Channels; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D015222:Sodium Channels; D000804:Angiotensin II; D004533:Egtazic Acid; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; C058819:calphostin C; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium