β-Adrenergic receptor agonist increases voltage-gated Na+ currents in medial prefrontal cortex pyramidal neurons

Combination antiretroviral therapy (cART) suppresses HIV-1 replication, improves immune function, and prolongs the life of people living with HIV (PLWH). However, cART also induces neurotoxicity that could complicate HIV-induced neurodegeneration while reduce its therapeutic efficacy in treating HIV/AIDS. Triumeq is a first-line cART regimen, which is co-formulated by three antiretroviral drugs (ARVs), lamivudine (3TC), abcavir (ABC), and dolutegravir (DTG). Little is known about potential side effects of ARVs on the brain (including those co-formulating Triumeq), and their mechanisms impacting neuronal activity. We assessed acute (in vitro) and chronic (in vivo) effects of Triumeq and co-formulating ARVs on pyramidal neurons in rat brain slices containing the medial prefrontal cortex (mPFC) using patch-clamp recording approaches. We found that acute Triumeq or 3TC in vitro significantly increased firing of mPFC neurons in a concentration- and time-dependent manner. This neuronal hyperactivity was associated with enhanced Ca2+ influx through voltage-gated Ca2+ channels (VGCCs). Additionally, chronic treatment with Triumeq in vivo for 4 weeks (4 wks) also significantly increased firing and Ca2+ influx via VGCCs in mPFC neurons, which was not shown after 2 wks treatment. Such mPFC neuronal hyperexcitability was not found after 4 weeks treatments of individual ARVs. Further, chronic Triumeq exposure in vivo significantly enhanced mRNA expression of low voltage-activated (LVA) L-type Ca2+ channels (Cav1.3 L-channels), while changes in high voltage-activated (HVA) Cav1.2 L-channels were not observed. Collectively, these novel findings demonstrate that chronic cART induces hyperexcitability of mPFC pyramidal neurons by abnormally promoting VGCC overactivation/overexpression of VGCCs (including, but may not limited to, LVA-Cav1.3 L-channels), which could complicate HIV-induced neurotoxicity, and ultimately may contribute to HIV-associated neurocognitive disorders (HAND) in PLWH. Determining additional target(s) of cART in mPFC pyramidal neurons may help to improve the therapeutic strategies by minimizing the side effects of cART for treating HIV/AIDS.

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Effects of β3-adrenergic receptor stimulation on the resting holding current of medial prefrontal cortex pyramidal neurons in young rats

Neuroscience Letters ◽

10.1016/j.neulet.2019.01.022 ◽

2019 ◽

Vol 698 ◽

pp. 192-197 ◽

Cited By ~ 2

Author(s):

Katarzyna Grzelka ◽

Maciej Gawlak ◽

Katarzyna Czarzasta ◽

Paweł Szulczyk

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Adrenergic Receptor ◽

Pyramidal Neurons ◽

Receptor Stimulation ◽

Young Rats

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Somatic and dendritic perforated-patch recordings reveal β-adrenergic receptor-induced depolarization in medial prefrontal cortex pyramidal neurons

Acta Neurobiologiae Experimentalis ◽

10.21307/ane-2017-015 ◽

2016 ◽

Vol 76 (2) ◽

pp. 158-164 ◽

Cited By ~ 2

Author(s):

Bartłomiej Szulczyk

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Adrenergic Receptor ◽

Pyramidal Neurons ◽

Perforated Patch

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The β2-Subunit of Voltage-Gated Calcium Channels Regulates Cardiomyocyte Hypertrophy

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.704657 ◽

2021 ◽

Vol 8 ◽

Author(s):

Simone Pickel ◽

Yiliam Cruz-Garcia ◽

Sandra Bandleon ◽

Katalin Barkovits ◽

Cornelia Heindl ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Adrenergic Receptor ◽

Receptor Agonist ◽

Cardiomyocyte Hypertrophy ◽

Calpain Activity ◽

Voltage Gated ◽

Calcium Dependent ◽

Voltage Gated Calcium Channels ◽

Adrenergic Receptor Agonist

L-type voltage-gated calcium channels (LTCCs) regulate crucial physiological processes in the heart. They are composed of the Cavα1 pore-forming subunit and the accessory subunits Cavβ, Cavα2δ, and Cavγ. Cavβ is a cytosolic protein that regulates channel trafficking and activity, but it also exerts other LTCC-independent functions. Cardiac hypertrophy, a relevant risk factor for the development of congestive heart failure, depends on the activation of calcium-dependent pro-hypertrophic signaling cascades. Here, by using shRNA-mediated Cavβ silencing, we demonstrate that Cavβ2 downregulation enhances α1-adrenergic receptor agonist-induced cardiomyocyte hypertrophy. We report that a pool of Cavβ2 is targeted to the nucleus in cardiomyocytes and that the expression of this nuclear fraction decreases during in vitro and in vivo induction of cardiac hypertrophy. Moreover, the overexpression of nucleus-targeted Cavβ2 in cardiomyocytes inhibits in vitro-induced hypertrophy. Quantitative proteomic analyses showed that Cavβ2 knockdown leads to changes in the expression of diverse myocyte proteins, including reduction of calpastatin, an endogenous inhibitor of the calcium-dependent protease calpain. Accordingly, Cavβ2-downregulated cardiomyocytes had a 2-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Cavβ2-downregulated cells abolished the enhanced α1-adrenergic receptor agonist-induced hypertrophy observed in these cells. Our findings indicate that in cardiomyocytes, a nuclear pool of Cavβ2 participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Cavβ2 during cardiomyocyte hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.

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