Pretreatment with Nonselective Cationic Channel Inhibitors Blunts the PACAP-Induced Increase in Guinea Pig Cardiac Neuron Excitability

Merriam, Laura A.; Roman, Carolyn W.; Baran, Caitlin N.; Girard, Beatrice M.; May, Víctor; Parsons, Rodney L.

doi:10.1007/s12031-012-9763-z

Cited by 9 publications

(10 citation statements)

References 23 publications

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“…We showed that a PACAP-induced calcium influx is a critical step in the peptide modulation of cardiac neuron excitability (50). Previously, calcium influx through a PACAP-enhanced, receptor-operated nonselective cationic channel was suggested (37). However, as described above, the present results indicate that a PACAP-enhanced inward current through a Ni 2ϩ -sensitive channel such as T-type or R-type calcium channels more likely contributes to the peptide-induced increase in excitability.…”

Section: Discussionmentioning

confidence: 89%

“…Transcript levels were determined for the three different T-type calcium channel isoforms (Cav3.1, Cav3.2, and Cav3.3) from laser captured (PALM Microlaser Technologies, Thornwood, NY) cardiac ganglia (37). In brief, clusters of cardiac ganglion cells (ganglia) were identified on nine atrial cardiac ganglia whole mount preparations.…”

Section: Animalsmentioning

confidence: 99%

“…However, the calcium influx pathway was not identified (50). A voltagedependent calcium channel (VDCC) was thought not to be the pathway as PACAP decreased whole cell barium currents (50); instead the calcium influx was suggested to occur through receptor-activated nonselective cationic channels since different putative nonselective cationic channel inhibitors could blunt the PACAP-induced increase in cardiac neuron excitability (37). However, many of these putative nonselective cationic channel inhibitors also can block voltage-dependent calcium channels, including T-type channels (43).…”

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confidence: 99%

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Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability

Tompkins

Merriam

Girard

et al. 2015

American Journal of Physiology-Cell Physiology

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is a potent intercellular signaling molecule involved in multiple homeostatic functions. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, making them a unique system to establish mechanisms underlying PACAP modulation of neuronal function. Calcium influx is required for the PACAP-increased cardiac neuron excitability, although the pathway is unknown. This study tested whether PACAP enhancement of calcium influx through either T-type or R-type channels contributed to the modulation of excitability. Real-time quantitative polymerase chain reaction analyses indicated transcripts for Cav3.1, Cav3.2, and Cav3.3 T-type isoforms and R-type Cav2.3 in cardiac neurons. These neurons often exhibit a hyperpolarization-induced rebound depolarization that remains when cesium is present to block hyperpolarization-activated nonselective cationic currents (Ih). The T-type calcium channel inhibitors, nickel (Ni(2+)) or mibefradil, suppressed the rebound depolarization, and treatment with both drugs hyperpolarized cardiac neurons by 2-4 mV. Together, these results are consistent with the presence of functional T-type channels, potentially along with R-type channels, in these cardiac neurons. Fifty micromolar Ni(2+), a concentration that suppresses currents in both T-type and R-type channels, blunted the PACAP-initiated increase in excitability. Ni(2+) also blunted PACAP enhancement of the hyperpolarization-induced rebound depolarization and reversed the PACAP-mediated increase in excitability, after being initiated, in a subset of cells. Lastly, low voltage-activated currents, measured under perforated patch whole cell recording conditions and potentially flowing through T-type or R-type channels, were enhanced by PACAP. Together, our results suggest that a PACAP-enhanced, Ni(2+)-sensitive current contributes to PACAP-induced modulation of neuronal excitability.

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Section: Discussionmentioning

confidence: 89%

Section: Animalsmentioning

confidence: 99%

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confidence: 99%

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Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability

Tompkins

Merriam

Girard

et al. 2015

American Journal of Physiology-Cell Physiology

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“…Therefore, FFA was proposed as a potentially effective agent for the treatment of epilepsy. FFA (30 μM) reduces the peptide-induced intra-cardiac neuron firing rate (Merriam et al ., 2012), which may involve the TRPC channel inhibition. A reduction of firing rate by FFA (20 μM) was also reported in GABAergic neurons, possibly through TRP current inhibition (Lee et al ., 2011b).…”

Section: Impact Of Ion Channels Modulation By Ffa On Physiologicalmentioning

confidence: 99%

Flufenamic acid as an ion channel modulator

Guinamard

Simard

Negro

2013

Pharmacology & Therapeutics

125

113

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Flufenamic acid has been known since the 1960s to have anti-inflammatory properties attributable to the reduction of prostaglandin synthesis. Thirty years later, flufenamic acid appeared to be an ion channel modulator. Thus, while its use in medicine diminished, its use in ionic channel research expanded. Flufenamic acid commonly affects non-selective cation channels and chloride channels, but also modulates potassium, calcium and sodium channels with effective concentrations ranging from 10-6 M in TRPM4 channel inhibition to 10-3 M in two-pore outwardly rectifying potassium channel activation. Because flufenamic acid effects develop and reverse rapidly, it is a convenient and widely used tool. However, given the broad spectrum of its targets, experimental results have to be interpreted cautiously. Here we provide an overview of ion channels targeted by flufenamic acid to aid in interpreting its effects at the molecular, cellular, and systems levels. If it is used with good practices, flufenamic acid remains a useful tool for ion channel research. Understanding the targets of FFA may help reevaluate its physiological impacts and revive interest in its therapeutic potential.

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“…In PC-12 cells, PACAP signaling also includes IP 3 production and TRP channel activation, but in this case the species implicated (i.e., TRPC1) is activated by depletion of calcium from the endoplasmic reticulum (35). Recently, TRPC channels have been suggested to underlie the excitatory effects of PACAP on cardiac neurons, excitation that was suppressed by SKF96365 (31). Further, corroborating an important role for TRPC channels in regulating CSN responses to PACAP, multiple TRPC channel proteins (TRPC1/3/4/5/6/7) are strongly expressed on glomus cells and/or the petrosal afferent nerve terminals that innervate them (5).…”

Section: Discussionmentioning

confidence: 99%

Stress peptide PACAP engages multiple signaling pathways within the carotid body to initiate excitatory responses in respiratory and sympathetic chemosensory afferents

Roy

Derakhshan

Wilson

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Consistent with a critical role in respiratory and autonomic stress responses, the carotid bodies are strongly excited by pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide implicated in stress responses throughout the sympathetic nervous system. PACAP excites isolated carotid body glomus cells via activation of PAC1 receptors, with one study suggesting PAC1-induced excitation is due entirely to protein kinase A (PKA)-mediated inhibition of TASK channels. However, in other systems, PAC1 is known to be coupled to multiple intracellular signaling pathways, including PKA, phospholipase C (PLC), phospholipase D (PLD), and protein kinase C (PKC), that trigger multiple downstream effectors including increased Ca²⁺ mobilization, inhibition of various K⁺ channels, and activation of nonselective cation channels. This study tests if non-PKA/TASK channel signaling helps mediate the stimulatory effects of PACAP on the carotid body. Using an ex vivo arterially perfused rat carotid body preparation, we show that PACAP-38 stimulates carotid sinus nerve activity in a biphasic manner (peak response, falling to plateau). PKA blocker H-89 only reduced the plateau response (~41%), whereas the TASK-1-like K⁺ channel blocker/transient receptor potential vanilloid 1 channel agonist anandamide only inhibited the peak response (~48%), suggesting involvement of additional pathways. The PLD blocker CAY10594 significantly inhibited both peak and plateau responses. The PLC blocker U73122 decimated both peak and plateau responses. Brefeldin A, a blocker of Epac (cAMP-activated guanine exchange factor, reported to link Gs-coupled receptors with PLC/PLD), also reduced both phases of the response, as did blocking signaling downstream of PLC/PLD with the PKC inhibitors chelerythrine chloride and GF109203X. Suggesting the involvement of non-TASK ion channels in the effects of PACAP, the A-type K⁺ channel blocker 4-aminopyridine, and the putative transient receptor potential channel (TRPC)/T-type calcium channel blocker SKF96365 each significantly inhibited the peak and steady-state responses. These data suggest the stimulatory effect of PACAP-38 on carotid body sensory activity is mediated through multiple signaling pathways: the PLC-PKC pathways predominates, with TRPC and/or T-type channel activation and Kv channel inactivation; only partial involvement is attributable to PKA and PLD activation.

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Pretreatment with Nonselective Cationic Channel Inhibitors Blunts the PACAP-Induced Increase in Guinea Pig Cardiac Neuron Excitability

Cited by 9 publications

References 23 publications

Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability

Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability

Flufenamic acid as an ion channel modulator

Stress peptide PACAP engages multiple signaling pathways within the carotid body to initiate excitatory responses in respiratory and sympathetic chemosensory afferents

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