Abstract
The L-type Ca2+ channel Cav1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving b-adrenergic receptors (bARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser1928 in Cav1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser1928 is not required for regulation of cardiac Cav1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Cav1.2 and enhancement of its activity by the β2-adrenergic receptor (β2AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Cav1.2 by PKA in cardiomyocytes and hippocampal neurons.
| Original language | English (US) |
|---|---|
| Article number | aaf9659 |
| Journal | Science Signaling |
| Volume | 10 |
| Issue number | 463 |
| DOIs | |
| State | Published - Jan 24 2017 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons. / Qian, Hai; Patriarchi, Tommaso; Price, Jennifer L.; Matt, Lucas; Lee, Boram; Nieves-Cintrón, Madeline; Buonarati, Olivia R.; Chowdhury, Dhrubajyoti; Nanou, Evanthia; Nystoriak, Matthew A.; Catterall, William A.; Poomvanicha, Montatip; Hofmann, Franz; Navedo, Manuel F.; Hell, Johannes W.
In: Science Signaling, Vol. 10, No. 463, aaf9659, 24.01.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons
AU - Qian, Hai
AU - Patriarchi, Tommaso
AU - Price, Jennifer L.
AU - Matt, Lucas
AU - Lee, Boram
AU - Nieves-Cintrón, Madeline
AU - Buonarati, Olivia R.
AU - Chowdhury, Dhrubajyoti
AU - Nanou, Evanthia
AU - Nystoriak, Matthew A.
AU - Catterall, William A.
AU - Poomvanicha, Montatip
AU - Hofmann, Franz
AU - Navedo, Manuel F.
AU - Hell, Johannes W.
PY - 2017/1/24
Y1 - 2017/1/24
N2 - The L-type Ca2+ channel Cav1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving b-adrenergic receptors (bARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser1928 in Cav1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser1928 is not required for regulation of cardiac Cav1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Cav1.2 and enhancement of its activity by the β2-adrenergic receptor (β2AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Cav1.2 by PKA in cardiomyocytes and hippocampal neurons.
AB - The L-type Ca2+ channel Cav1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving b-adrenergic receptors (bARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser1928 in Cav1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser1928 is not required for regulation of cardiac Cav1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Cav1.2 and enhancement of its activity by the β2-adrenergic receptor (β2AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Cav1.2 by PKA in cardiomyocytes and hippocampal neurons.
UR - http://www.scopus.com/inward/record.url?scp=85011568211&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011568211&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aaf9659
DO - 10.1126/scisignal.aaf9659
M3 - Article
C2 - 28119465
AN - SCOPUS:85011568211
VL - 10
JO - Science Signaling
JF - Science Signaling
SN - 1937-9145
IS - 463
M1 - aaf9659
ER -