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The role of Ca 2+ influx pathways in voltage‐dependent STOC production (853.10)
Author(s) -
Hashad Ahmed,
Mazumda Neil,
Harraz Osama,
Welsh Donald
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.853.10
Subject(s) - depolarization , chemistry , biophysics , membrane potential , electrophysiology , stimulation , nifedipine , voltage clamp , calcium , endocrinology , neuroscience , biochemistry , biology , organic chemistry
Ca 2+ sparks are generated in a voltage dependent manner to initiate spontaneous transient outward currents (STOC) that antagonize arterial constriction. In the present study, we defined the mechanisms by which membrane depolarization increases Ca 2+ sparks and subsequent STOC production. Using perforated patch clamp electrophysiology and rat cerebral arterial myocytes, we monitored STOC in the presence and absence of agents that modulate Ca 2+ entry pathways. Beginning with the Ca V 3.2 inhibitor Ni 2+ , STOC frequency decreased in cells held at hyperpolarized voltage (‐40 mV). In contrast, Ca V 1.2 inhibition with nifedipine suppressed STOC frequency at depolarized potential (‐20 mV). These findings are consistent with the voltage‐dependent profiles of L‐ and T‐type Ca 2+ channels; and were replicated in a computational model of Ca 2+ spark production. Upon concomitant Ca V 1.2 and Ca V 3.2 blockade, we further observed residual voltage‐independent STOC production. This residual component was insensitive to stimulation or inhibition of TRPV4 channels. Further ongoing work aims to investigate the involvement of other Ca 2+ entry routes. In summary, distinct Ca 2+ channel isoforms govern the voltage‐dependency of STOC production and they do so at defined membrane potentials. These findings have important mechanistic implications to the basis of negative feedback, arterial tone regulation and blood flow control.