R-Type Voltage-Gated Ca2+ Channels in Cardiac and Neuronal Rhythmogenesis

During the past decades, an increasing number of ion channel and transporter types have been identified acting together to produce cardiac and neuronal pacemaker action potentials. The basis of pacemaker activity was understood in more detail by using single-microelectrode recordings on cells isolated from pacemaker regions. Meanwhile, this powerful technique was complemented by computer modeling and recombinant technologies, including gene inactivation of ion channels and transporters, which may be involved in the generation of the electrical activity of pacemaker cells. Several genes of the voltage-gated Ca2+ channel (VGCC) family have been ablated, and their role in cardiac and neuronal pacemaking is compared in the present summary, focusing on the role of murine R-type voltage-gated Ca2+ channels encoded by cacna1e and expressing the ion conducting subunit Ca(v)2.3

Surgical Approaches in Psychiatry: A Survey of the World Literature on Psychosurgery

Brain surgery to promote behavioral or affective changes in humans remains one of the most controversial topics at the interface of medicine, psychiatry, neuroscience, and bioethics. Rapid expansion of neuropsychiatric deep brain stimulation has recently revived the field and careful appraisal of its 2 sides is warranted: namely, the promise to help severely devastated patients on the one hand and the dangers of premature application without appropriate justification on the other. Here, we reconstruct the vivid history of the field and examine its present status to delineate the progression from crude freehand operations into a multidisciplinary treatment of last resort. This goal is accomplished by a detailed reassessment of numerous case reports and small-scale open or controlled trials in their historical and social context. The different surgical approaches, their rationale, and their scientific merit are discussed in a manner comprehensible to readers lacking extensive knowledge of neurosurgery or psychiatry, yet with sufficient documentation to provide a useful resource for practitioners in the field and those wishing to pursue the topic further

Multiple nickel-sensitive targets elicit cardiac arrhythmia in isolated mouse hearts after pituitary adenylate cyclase-activating polypeptide-mediated chronotropy

The pituitary adenylate cyclase-activating polypeptide (PACAP)-27 modulates various biological processes, from the cellular level to function specification. However, the cardiac actions of this neuropeptide are still under intense studies. Using control (+I+) and mice lacking (-1-) either R-type (Ca(v)2.3) or T-type (Ca(v)3.2) Ca2(+) channels, we investigated the effects of PACAP-27 on cardiac activity of spontaneously beating isolated perfused hearts. Superfusion of PACAP-27 (20 nM) caused a significant increase of baseline heart frequency in Cav2.3(+1+) (156.9 10.8 to 239.4 23.4 bpm; p < 0.01) and Cav2.3(-1-) (190.3 +/- 26.4 to 270.5 +/- 25.8 bpm; p < 0.05) hearts. For Cav3.2, the heart rate was significantly increased in Cav3.2(-l-) (133.1 +/- 8.5 bpm to 204.6 +/- 27.9 bpm; p <0.05) compared to Cav3.2(+I+) hearts (185.7 +/- 11.2 bpm to 209.3 +/- 22.7 bpm). While the P wave duration and QTc interval were significantly increased in Cav2.3(+1+) and Cav2.3(-I-) hearts following PACAP-27 superfusion, there was no effect in Cav3.2(+I+) and Cav3.2(-l-) hearts. The positive chronotropic effects observed in the four study groups, as well as the effect on P wave duration and QTc interval were abolished in the presence of Ni2+ (50,mu M) and PACAP-27 (20 nM) in hearts from Cav2.3(+I+) and Cav2.3(-I-) mice. In addition to suppressing PACAP's response, Ni2+ also induced conduction disturbances in investigated hearts. In conclusion, the most Ni2+-sensitive Ca2+ channels (R-and T-type) may modulate the PACAP signaling cascade during cardiac excitation in isolated mouse hearts, albeit to a lesser extent than other Ni2+-sensitive targets. (C) 2016 Published by Elsevier Ltd

Cav2.3 (R-Type) Calcium Channels are Critical for Mediating Anticonvulsive and Neuroprotective Properties of Lamotrigine In Vivo

Background/Aims: Lamotrigine (LTG) is a popular modern antiepileptic drug (AED), however, its mechanism of action has yet to be fully understood, as it is known to modulate many members of several ion channel families. In heterologous systems, LTG inhibits Cav2.3 (R-type) calcium currents, which contribute to kainic-acid- (KA) induced epilepsy in vivo. To gain insight into the role of R-type currents in LTG drug action in vivo, we compared the effects of LTG to topiramate and lacosamide in Cav2.3-deficient mice and controls on KA-induced seizures. Methods: Behavioral seizure rating and quantitative electrocorticography were performed after injection of 20 mg/kg [and 30 mg/kg] KA. One hour before KA injection, mice were pretreated with either 30 mg/kg LTG, 50 mg/kg topiramate (TPM) or 30 mg/kg lacosamide (LSM). Results: Ablation of Cav2.3 reduced total seizure scores by 28.6% (p=0.0012) and pretreatment with LTG reduced seizure activity of control mice by 23.2% (p=0.02). In Cav2.3-deficient mice LTG pretreatment increased seizure activity by 22.1% (p=0.018) and increased the percentage of degenerated CA1 pyramidal neurons (p=0.02). All three tested AEDs reduced seizure activity in control mice, however only the non-calcium channel modulating AED, LSM had an anticonvulsive effect in Cav2.3-deficient mice. Furthermore LTG altered electrocorticographic parameters differently in the two genotypes, decreasing relative power of ictal spikes in control mice compared to Cav2.3-defcient mice. Conclusion: These findings give first in vivo evidence for an essential role for Cav2.3 in LTG pharmacology and shed light on a paradoxical effect of LTG in their absence. Furthermore, LTG appears to promote ictal activity in Cav2.3-deficient mice resulting in increased neurotoxicity in the CA1 region. This paradoxical mechanism, possibly reflecting rebound hyperexcitation of pyramidal CA1 neurons after increased inhibition, may be key in understanding LTG-induced seizure aggravation, observed in clinical practice