Opposing Roles of Voltage-Gated Ca²⁺Channels in Neuronal Control of Regenerative Patterning

Abstract

There is intense interest in developing methods to regulate proliferation and differentiation of stem cells into neuronal fates for the purposes of regenerative medicine. One way to do this is through in vivo pharmacological engineering using small molecules. However, a key challenge is identification of relevant signaling pathways and therein druggable targets to manipulate stem cell behavior efficiently in vivo.

Utilizing the planarian voltage-gated ion channel transcriptome to resolve a role for a Ca 2+ channel in neuromuscular function and regeneration

“…Therefore, the discovery that planarian muscle cells express a suite of ‘position control genes’ (Witchley et al, 2013) refocuses interest on observations that Ca 2+ signaling events and voltage-operated Ca 2+ (Ca v ) channels impact AP patterning (Nogi et al, 2009; Zhang et al, 2011). …”

“…Knockdown was performed over several feeding/regeneration cycles (Nogi et al, 2009; Zhang et al, 2011). Ca v fragments were subcloned into the IPTG-inducible pDONRdT7 vector and transfected into RNaseIII deficient HT115 E. coli .…”

“…Ca 2+ signaling events have been shown to play a role in determination of anterior-posterior polarity during the early phase of planarian tissue regeneration: several drugs that perturb Ca 2+ homeostasis cause polarity defects if applied contemporaneously, or shortly after, tissue amputation (Nogi et al, 2009). Knockdown ( in vivo RNAi) of specific voltage-operated Ca 2+ channels can differentially impact regenerative polarity outcomes (Zhang et al, 2011). …”

Kinetic profiling an abundantly expressed planarian serotonergic GPCR identifies bromocriptine as a perdurant antagonist

“…For example, the ability to combine genetic ( in vivo RNAi) and pharmacological manipulations in this system has provided insight into the pathways engaged by the anthelmintic praziquantel (PZQ) in this model (Nogi et al., 2009, Zhang et al., 2011, Chan et al., 2014), as well as the identification of ligands that phenocopy PZQ action which may augur anthelmintic efficacy (Chan et al., 2014, Chan et al., 2015). Serotonergic G protein coupled receptors (GPCRs) are one such class of targets, highlighting the importance of investigating their pharmacological signatures and roles in flatworm biology.…”

Design and synthesis of molecular probes for the determination of the target of the anthelmintic drug praziquantel

“…22 Although the molecular target of PZQ remains unknown, a number of lines of evidence suggests that it disrupts cellular Ca 2+ homeostasis by affecting voltage gated Ca 2+ channel function. 23– 26 The lack of an efficient general small-scale method for developing molecular probes of exceptional high optical purity limits our ability to readily prepare specific molecular probes based on the active and inactive soluble configuration of the PZQ pharmacophore. Molecular probes of this type may lead to an improved understanding of the mode of action of PZQ on schistosomes.…”