Kevin Luykenaar

Kevin Luykenaar Postdoctorate Fellow
BSc Cellular, Molecular and Microbial Biology, Univ. Calgary 2001
PhD Cardiovascular & Respiratory Sciences, Univ. Calgary 2009
PhD Dissertation: Rho-mediated suppression of KDR current in cerebral arteries

Current Gig:
Leaders in Medicine Program
University of Calgary
Calgary AB
kdluyken@ucalgary.ca

Training
2009
PhD in Smooth Muscle Physiology
University of Calgary
Calgary Alberta
Supervisor: Dr. D. Welsh

2009 -
Postdoctorate
University of Calgary
Calgary Alberta
Supervisors: Dr. R.W. Turner, G Zamponi

Awards
PhD
Graduate program travel award, 2004
Graduate Research Scholarship, 2005
Graduate Research Scholarship, 2006
“Focus on Stroke” Doctoral Research Award - Heart & Stroke Foundation Canada, 2006
Cardiovascular Research Recognition Award - American Physiological Society, 2007

PDF
AHFMR Fellowship
Medical School Entrance

Research Focus: Kv4 potassium channel function

Approach:

Electrophysiology in vitro, pharmacology, molecular biology

Preparations:

Expression systems, in vitro slice preparations

Below are short summaries of my publications.

PhD Thesis research:
My PhD work centered on the regulation of delayed rectifier and inward rectifier potassium currents in cerebral arterial smooth muscle cells.

ACh-evoked relaxations of basilar artery

In this study, we examined the mechanisms by which pyrimidine nucleotides, such as UTP, elicit the constriction of cerebral arteries. We found that a significant part of the constriction was dependent on smooth muscle depolarization and the subsequent influx of contractile calcium through voltage-gated calcium channels. We showed that UTP-induced depolarization involves the suppression of a delayed rectifier potassium (K-DR ) current. Intriguingly, K-DR current suppression and arterial depolarization/constriction were dependent on Rho signaling. PDF

In this work, a dominant-negative molecular strategy was used in conjunction with pressure myography to explore the role of voltage-dependent Kv1 potassium channels in vasoregulation. Expression of mutant Kv1.5 dramatically enhanced, whereas wild-type subunit expression markedly suppressed, myogenic depolarization and constriction. These findings provide the first molecular evidence that Kv1-containing delayed rectifier potassium channels are important for control of arterial diameter and, thereby, peripheral vascular resistance and blood flow. PDF

This study sought to define whether inward rectifying potassium (K IR) channels were modulated by vasoactive stimuli known to depolarize and constrict intact cerebral arteries. We found that a hyposmotic challenge elicited a rapid and sustained inhibition of K IR current through a PKC dependent pathway. These findings suggest that, by modulating PKC, mechanical stimuli can regulate K IR activity and consequently the electrical and mechanical state of intact cerebral arteries. PDF

RhoA is a key regulatory protein in agonist-induced responses in vascular smooth muscle that may be negatively regulated by PKA and PKG phosphorylation. This study tested whether such a mechanism was important in regulating vascular tone within the cerebral circulation. We found that PKA and PKG pathways reduce UTP-mediated constriction of cerebral arteries in part by minimizing a RhoA-mediated suppression of a delayed rectifier potassium current. PDF

In principle, the negative slope conductance of K IR channels could enable these channels to ‘amplify' responses initiated by other potassium conductances. We showed that blocking K IR limits the ability of potassium channel activators to dilate cerebral and coronary arteries. This attenuation was absent in mesenteric arteries where smooth muscle K IR channels are poorly expressed. These findings highlight the fact that subtle biophysical properties of K IR have a substantive role in enabling agonists to alter the electrical state of a multilayered artery. PDF

This work focused on the mechanism by which Rho-kinase could modulate the activity of K DR channels. We found that Rho-kinase was essential in mediating actin polymerization in response to UTP and that both Rho-kinase inhibition and actin disruption prevented K DR current modulation. Consistent with this, both Rho-kinase inhibition and actin disruption significantly attenuated UTP-induced depolarization and constriction of cerebral arteries. PDF

Postdoctoral research:
My work is focused on the properties of Kv4 potassium channels and how calcium influx can modulate the kinetic properties via interactions with a calcium sensor protein.

Peer-Reviewed Publications

Luykenaar KD, Brett SE, Wu BN, Wiehler WB, and DG Welsh. (2004) Pyrimidine nucleotides suppress K DR and depolarize rat cerebral arteries by activating Rho-kinase. Am J of Physiol Heart and Circ Physiol 286: H1088-H1100. PDF

Chen TT, Luykenaar KD , Walsh EJ, Walsh MP, Cole WC. (2006) Key role of Kv1 channels in vasoregulation. Circ Res 99(1): 53-60. PDF

Luykenaar KD and DG Welsh. (2007) Activators of the PKA and PKG pathways attenuate RhoA-mediated suppression of the K DR current in cerebral arteries. Am J Physiol Heart Circ Physiol 292(6): H2654-63. PDF

Wu BN, Luykenaar KD , Brayden JE, Giles WR, Corteling RL, Wiehler WB, Welsh DG. (2007) Hyposmotic challenge inhibits inward rectifying K + channel in cerebral arterial smooth muscle cells. Am J Physiol Heart Circ Physiol 292(2): H1085-H1094, 2007. PDF

Smith PD, Brett SE, Luykenaar KD , Sandow SL, Marelli SP, Vigmond EJ, and DG Welsh. (2008) KIR channels function as electrical amplifiers in rat vascular smooth muscle. J Physiol 586(4): 1147-60. PDF

Luykenaar KD , Abd El-Rahman R, Walsh MP, and DG Welsh. (2009) Rho-kinase-mediated suppression of K DR current in cerebral arteries requires an intact actin cytoskeleton. Am J of Physiol Heart and Circ Physiol, In Press. PDF

Key Abstracts

Luykenaar KD , Wu BN, and DG Welsh. RhoA pathway mediates UTP-induced inhibition of K DR in cerebral myocytes. Biophysical Journal . 84: 420a, 2003 .

Wu BN, Giles WR, Brayden, JE, Luykenaar KD, Welsh DG. Mechanical stimuli inhibit inward rectifying potassium channels in cerebral myocytes. Biophysical Journal. 84:107a, 2003.

Luykenaar KD , Brett SE, Wu BN, Wiehler WB, Welsh DG. Pyrimidine nucleotides suppress K DR and depolarize rat cerebral arteries by activating Rho-kinase. The FASEB Journal. 18: A306, 2004.

Welsh DG, Wu BN, Giles WR, Brayden JE, Luykenaar KD, Wiehler WB. Inward rectifying potassium channels and the development of myogenic tone. The FASEB Journal. 18: A1085, 2004.

Diep HK, Vigmond EJ, Luykenaar KD, Segal SS. and DG Welsh. Defining electrical communication in skeletal muscle resistance arteries: a computational approach. Ion channels, genes and regulation in smooth muscle, Physiological Soc. 2005, Oxford University , Journal of Physiology.

Luykenaar KD and DG Welsh. PKA and PKG regulate RhoA-mediated suppression of K DR current in cerebral arteries. FASEB Journal 20(5): A1240, 2006.

Luykenaar KD, Wu BN, Brayden JE, Giles WR, Corteling RL and DG Welsh. Hyposmotic challenge inhibits inward rectifying potassium channels in cerebral arterial smooth muscle cells. FASEB Journal 21 (5): 599.19, 2007.

Luykenaar KD and DG Welsh. Rho-kinase-mediated suppression of K DR current in cerebral arteries requires an intact actin cytoskeleton. FASEB Journal 22: 965.12, 2008.

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