Arsalan Yousuf

Publications (3)10.19 Total impact

• Article: Concomitant facilitation of GABAA receptors and KV7 channels by the non-opioid analgesic flupirtine.

  Felicia Klinger, Petra Geier, Mario M Dorostkar, Giri K Chandaka, Arsalan Yousuf, Isabella Salzer, Helmut Kubista, Stefan Boehm
  [show abstract] [hide abstract]
  ABSTRACT: Flupirtine is a non-opioid analgesic that has been in clinical use for more than 20 years. It is characterized as a selective neuronal potassium channel opener (SNEPCO). Nevertheless, its mechanisms of action remain controversial and are the purpose of this study. Effects of flupirtine on native and recombinant voltage- and ligand-gated ion channels were explored in patch-clamp experiments using the following experimental systems: recombinant K(IR)3 and K(V)7 channels and α3β4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na(+), Ca(2+), inward rectifier K(+), K(V)7 K(+), and TRPV1 channels, as well as GABA(A), glycine, and ionotropic glutamate receptors expressed in rat dorsal root ganglion, dorsal horn and hippocampal neurons. Therapeutic flupirtine concentrations (≤10 µM) did not affect voltage-gated Na(+) or Ca(2+) channels, inward rectifier K(+) channels, nicotinic acetylcholine receptors, glycine or ionotropic glutamate receptors. Flupirtine shifted the gating of K(V)7 K(+) channels to more negative potentials and the gating of GABA(A) receptors to lower GABA concentrations. These latter effects were more pronounced in dorsal root ganglion and dorsal horn neurons than in hippocampal neurons. In dorsal root ganglion and dorsal horn neurons, the facilitatory effect of therapeutic flupirtine concentrations on K(V)7 channels and GABA(A) receptors was comparable, whereas in hippocampal neurons the effects on K(V)7 channels were more pronounced. These results indicate that flupirtine exerts its analgesic action by acting on both GABA(A) receptors and K(V)7 channels.
  British Journal of Pharmacology 12/2011; 166(5):1631-42. · 4.41 Impact Factor
• Source

  Available from: PubMed Central

  Article: Nucleotides control the excitability of sensory neurons via two P2Y receptors and a bifurcated signaling cascade.

  Arsalan Yousuf, Felicia Klinger, Klaus Schicker, Stefan Boehm
  [show abstract] [hide abstract]
  ABSTRACT: Nucleotides contribute to the sensation of acute and chronic pain, but it remained enigmatic which G protein-coupled nucleotide (P2Y) receptors and associated signaling cascades are involved. To resolve this issue, nucleotides were applied to dorsal root ganglion neurons under current- and voltage-clamp. Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uridine triphosphate (UTP), but not uridine diphosphate (UDP), depolarized the neurons and enhanced action potential firing in response to current injections. The P2Y(2) receptor preferring agonist 2-thio-UTP was equipotent to UTP in eliciting these effects. The selective P2Y(1) receptor antagonist MRS2179 largely attenuated the excitatory effects of ADP, but left those of 2-thio-UTP unaltered. Thus, the excitatory effects of the nucleotides were mediated by 2 different P2Y receptors, P2Y(1) and P2Y(2). Activation of each of these 2 receptors by either ADP or 2-thio-UTP inhibited currents through K(V)7 channels, on one hand, and facilitated currents through TRPV(1) channels, on the other hand. Both effects were abolished by inhibitors of phospholipase C or Ca(2+)-ATPase and by chelation of intracellular Ca(2+). The facilitation of TRPV(1), but not the inhibition K(V)7 channels, was prevented by a protein kinase C inhibitor. Simultaneous blockage of K(V)7 channels and of TRPV(1) channels prevented nucleotide-induced membrane depolarization and action potential firing. Thus, P2Y(1) and P2Y(2) receptors mediate an excitation of dorsal root ganglion neurons by nucleotides through the inhibition of K(V)7 channels and the facilitation of TRPV(1) channels via a common bifurcated signaling pathway relying on an increase in intracellular Ca(2+) and an activation of protein kinase C, respectively.
  Pain 05/2011; 152(8):1899-908. · 5.78 Impact Factor
• Article: Nucleotides excite sensory neurons via two P2Y receptors and a dual signaling cascade

  Arsalan Yousuf, Stefan Boehm