ORIGINAL RESEARCH—BASIC SCIENCE: T-Type (α1G) Low Voltage-Activated Calcium Channel Interactions with Nitric Oxide-Cyclic Guanosine Monophosphate Pathway and Regulation of Calcium Homeostasis in Human Cavernosal Cells

Authors


  • Part of this work was presented at the American Urological Association Annual Meeting in San Francisco, California, May 8–13, 2004. Abstract ♯1634. J Urol 2004;171:432.

Suresh C. Sikka, PhD, HCLD, Professor of Urology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-42, New Orleans, LA 70112-2699, USA. Tel: (504) 988-5179; Fax: (504) 988-5059; E-mail: ssikka@tulane.edu

ABSTRACT

Introduction.  Nitric oxide-cyclic guanosine monophosphate (NO-cGMP)-mediated relaxation of cavernosal smooth muscle during erection is accompanied by a decrease in intracellular calcium concentrations ([Ca2+]i). However, it is not known whether and how an increase in [Ca2+]i is responsible for (i) initiating smooth muscle contraction/detumescence following relaxation; and (ii) maintaining the penis in a flaccid state under nonstimulating conditions.

Aim.  To elucidate (i) the mechanism(s) of [Ca2+]i homeostasis regulation in human cavernosal smooth muscle cells (HCSMC); and (ii) how NO-cGMP interacts with such [Ca2+]i homeostasis.

Methods.  We evaluated the expression and function of both T-type and L-type Ca2+ channels in HCSMC by employing selective probes/inhibitors using various cellular and molecular techniques (e.g., reverse transcriptase and real-time polymerase chain reaction, cell proliferation assay, fura-2 Ca2+ fluorescence spectroscopy, enzyme-linked immuno-absorbent assay (ELISA)).

Main Outcome Measure.  We have demonstrated for the first time significant interactions of NO-cGMP with the T-type (α1G) Ca2+ channel in HCSMC.

Results.  Our results suggest that in addition to NO-induced rapid and transient decrease in [Ca2+]i that results in smooth muscle relaxation, NO-cGMP also enhanced mRNA expression of the T-type (α1G) Ca2+ channel resulting in delayed elevation of [Ca2+]i. This could be abolished by a selective T-channel blocker, NNC 55-0396. Another unique finding of this study is that dose-dependent HCSMC proliferation in vitro by NO is associated with the activation of the T-type (α1G) Ca2+ channel that regulates [Ca2+]i homeostasis in these cells.

Conclusions.  Human cavernosal cells express T-type (α1G) Ca2+ channels that are involved in maintaining [Ca2+]i homeostasis and regulation of NO-cGMP-induced smooth muscle relaxation–contraction responsible for penile erection, flaccidity, and tonicity. Targeting these Ca2+ channels may (i) associate various comorbidities with the onset of erectile dysfunction; (ii) provide a biochemical basis for differences between therapeutic profiles of various phosphodiesterase type 5 inhibitors, especially in nonresponders to current therapy; and (iii) provide biochemical basis in understanding mechanism(s) of drug tolerance. Zeng X, Keyser B, Li M, and Sikka SC. T-type (α1G) low voltage-activated calcium channel interactions with nitric oxide-cyclic guanosine monophosphate pathway and regulation of calcium homeostasis in human cavernosal cells. J Sex Med 2005;2:620–633.

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