Interplay among distinct Ca2+conductances drives Ca2+sparks/spontaneous transient outward currents in rat cerebral arteries.
Distinct Ca2+channels work in a coordinated manner to grade Ca2+spark/spontaneous transient outward currents (STOCs) in rat cerebral arteries. The relative contribution of each Ca2+channel to Ca2+spark/STOC production depends upon their biophysical properties and the resting membrane potential of smooth muscle. Na+/Ca2+exchanger, but not TRP channels, can also facilitate STOC production.



Ca2+sparks are generated in a voltage-dependent manner to initiate spontaneous transient outward currents (STOCs), events that moderate arterial constriction. In this study, we defined the mechanisms by which membrane depolarization increases Ca2+sparks and subsequent STOC production. Using perforated patch clamp electrophysiology and rat cerebral arterial myocytes, we monitored STOCs in the presence and absence of agents that modulate Ca2+entry. Beginning with CaV3.2 channel inhibition, Ni2+was shown to decrease STOC frequency in cells held at hyperpolarized (-40 mV) but not depolarized (-20 mV) voltages. In contrast, nifedipine, a CaV1.2 inhibitor, markedly suppressed STOC frequency at -20 mV but not -40 mV. These findings aligned with the voltage-dependent profiles of L- and T-type Ca2+channels. Furthermore, computational and experimental observations illustrated that Ca2+spark production is intimately tied to the activity of both conductances. Intriguingly, this study observed residual STOC production at depolarized voltages that was independent of CaV1.2 and CaV3.2. This residual component was insensitive to TRPV4 channel modulation and was abolished by Na+/Ca2+exchanger blockade. In summary, our work highlights that the voltage-dependent triggering of Ca2+sparks/STOCs is not tied to a single conductance but rather reflects an interplay among multiple Ca2+permeable pores with distinct electrophysiological properties. This integrated orchestration enables smooth muscle to grade Ca2+spark/STOC production and thus precisely tune negative electrical feedback.
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institute, University of Calgary, Alberta, Canada.
Ahmed M
AM
Hashad
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
Neil
N
Mazumdar
Department of Basic Sciences, Division of Pharmacology, Loma Linda University, CA, USA.
Monica
M
Romero
Department of Electrical and Computer Engineering, University of Calgary, Calgary, Alberta, Canada.
Anders
A
Nygren
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institute, University of Calgary, Alberta, Canada.|Department of Electrical and Computer Engineering, University of Calgary, Calgary, Alberta, Canada.
Kamran
K
Bigdely-Shamloo
Department of Pharmacology, University of Vermont, Burlington, VT, USA.
Osama F
OF
Harraz
California Northstate University College of Medicine, CA, USA.
Jose L
JL
Puglisi
Department of Electrical and Computer Engineering, University of Calgary, Calgary, Alberta, Canada.|LIRYC Institute and Lab IMB, University of Bordeaux, Bordeaux, France.
Edward J
EJ
Vigmond
Department of Basic Sciences, Division of Pharmacology, Loma Linda University, CA, USA.
Sean M
SM
Wilson
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institute, University of Calgary, Alberta, Canada.|Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
Donald G
0000-0001-5174-186X
DG
Welsh
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D005260:Female; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism
D015220:Calcium Channels; D019831:Sodium-Calcium Exchanger; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat
BKCa channels; Ca2+ channels; Ca2+ spark; cerebral arteries