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Biomedical subjects

Gerald M Herrera

Publications and source records attributed to Gerald M Herrera.

7 recordsLinked to original sources
PubMed2006

PACAP enhances mouse urinary bladder contractility and is upregulated in micturition reflex pathways after cystitis.

Pituitary adenylate cyclase-activating polypeptide (PACAP) elicits a transient contraction, sustained increase in the amplitude of spontaneous phasic contractions, and significantly increases the amplitude of nerve-mediated contractions in mouse urinary bladder smooth muscle (UBSM) strips. PACAP immunoreactivity (IR) is increased in micturition reflex pathways following cystitis. PACAP may contribute to altered sensation and bladder overactivity in the chronic bladder inflammatory syndrome, interstitial cystitis.

Animals↗
PubMed2005

Negative feedback regulation of nerve-mediated contractions by KCa channels in mouse urinary bladder smooth muscle.

When the urinary bladder is full, activation of parasympathetic nerves causes release of neurotransmitters that induce forceful contraction of the detrusor muscle, leading to urine voiding. The roles of ion channels that regulate contractility of urinary bladder smooth muscle (UBSM) in response to activation of parasympathetic nerves are not well known. The present study was designed to characterize the role of large (BK)- and small-conductance (SK) Ca(2+)-activated K(+) (K(Ca)) channels in regulating UBSM contractility in response to physiological levels of nerve stimulation in UBSM strips from mice. Nerve-evoked contractions were induced by electric field stimulation (0.5-50 Hz) in isolated strips of UBSM. BK and SK channel inhibition substantially increased the amplitude of nerve-evoked contractions up to 2.45 +/- 0.12- and 2.99 +/- 0.25-fold, respectively. When both SK and BK channels were inhibited, the combined response was additive. Inhibition of L-type voltage-dependent Ca(2+) channels (VDCCs) in UBSM inhibited nerve-evoked contractions by 92.3 +/- 2.0%. These results suggest that SK and BK channels are part of two distinct negative feedback pathways that limit UBSM contractility in response to nerve stimulation by modulating the activity of VDCCs. Dysfunctional regulation of UBSM contractility by alterations in BK/SK channel expression or function may underlie pathologies such as overactive bladder.

Animals↗
PubMed2003

Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel.

Small conductance, calcium-activated potassium (SK) channels have an important role in determining the excitability and contractility of urinary bladder smooth muscle. Here, the role of the SK isoform SK3 was examined by altering expression levels of the SK3 gene using a mouse model that conditionally overexpresses SK3 channels (SK3T/T). Prominent SK3 immunostaining was found in both the smooth muscle (detrusor) and urothelium layers of the urinary bladder. SK currents were elevated 2.4-fold in isolated myocytes from SK3T/T mice. Selective suppression of SK3 expression by dietary doxycycline (DOX) decreased SK current density in isolated myocytes, increased phasic contractions of isolated urinary bladder smooth muscle strips and exposed high affinity effects of the blocker apamin of the SK isoforms (SK1-3), suggesting an additional participation from SK2 channels. The role of SK3 channels in urinary bladder function was assessed using cystometry in conscious, freely moving mice. The urinary bladders of SK3T/T had significantly greater bladder capacity, and urine output exceeded the infused saline volume. Suppression of SK3 channel expression did not alter filling pressure, threshold pressure or bladder capacity, but micturition pressure was elevated compared to control mice. However, SK3 suppression did eliminate excess urine production and caused a marked increase in non-voiding contractions. The ability to examine bladder function in mice in which SK3 channel expression is selectively altered reveals that these channels have a significant role in the control of non-voiding contractions in vivo. Activation of these channels may be a therapeutic approach for management of non-voiding contractions, a condition which characterizes many types of urinary bladder dysfunctions including urinary incontinence.

Animals↗
PubMed2003

Ca2+ sparks and K(Ca) channels: novel mechanisms to relax urinary bladder smooth muscle.

Negative feedback pathways that relax and stabilize UBSM are critical to the proper functioning of the urinary bladder. The complex interactions between K(Ca) channels and RyRs are just beginning to be unraveled. The consequences of SK, BK, and RyR dysfunction would increase cell excitability and lead to urinary bladder instability. Although each of these channels is a potential target for the development of therapeutics to treat urinary incontinence, SK is of special interest, since this SK isoform does not appear to be present in vascular smooth muscle.

Animals↗
PubMed2002

Differential regulation of SK and BK channels by Ca(2+) signals from Ca(2+) channels and ryanodine receptors in guinea-pig urinary bladder myocytes.

Small-conductance (SK) and large-conductance (BK) Ca(2+)-activated K(+) channels are key regulators of excitability in urinary bladder smooth muscle (UBSM) of guinea-pig. The overall goal of this study was to define how SK and BK channels respond to Ca(2+) signals from voltage-dependent Ca(2+) channels (VDCCs) in the surface membrane and from ryanodine-sensitive Ca(2+) release channels or ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) membrane. To characterize the role of SK channels in UBSM, the effects of the SK channel blocker apamin on phasic contractions were examined. Apamin caused a dose-dependent increase in the amplitude of phasic contractions over a broad concentration range (10(-10) to 10(-6) M). To determine the effects of Ca(2+) signals from VDCCs and RyRs to SK and BK channels, whole cell membrane current was measured in isolated myocytes bathed in physiological solutions. Depolarization (-70 to +10 mV for 100 ms) of isolated myocytes caused an inward Ca(2+) current (I(Ca)), followed by an outward current. The outward current was reduced in a dose-dependent manner by apamin (10(-10) to 10(-6) M), and designated I(SK). I(SK) had a mean amplitude of 53.8 +/- 6.1 pA or approximately 1.4 pA pF(-1) at +10 mV. The amplitude of I(SK) correlated with the peak I(Ca). Blocking I(Ca) abolished I(SK). In contrast, I(SK) was insensitive to the RyR blocker ryanodine (10 microM). These data indicate that Ca(2+) signals from VDCCs, but not from RyRs, activate SK channels. BK channel currents (I(BK)) were isolated from other currents by using the BK channel blockers tetraethylammonium ions (TEA(+); 1 mM) or iberiotoxin (200 nM). Voltage steps evoked transient and steady-state I(BK) components. Transient BK currents have previously been shown to result from BK channel activation by local Ca(2+) release through RyRs ('Ca(2+) sparks'). Transient BK currents were inhibited by ryanodine (10 microM), as expected, and had a mean amplitude of 152.6 pA at +10 mV. The mean number of transient BK currents during a voltage step (range 0 to 3) correlated with I(Ca). There was a long delay (52.4 +/- 2.7 ms) between activation of I(Ca) and the first transient BK current. In contrast, ryanodine did not affect the steady-state BK current (mean amplitude 135.4 pA) during the voltage step. The steady-state BK current was reduced 95 % by inhibition of VDCCs, suggesting that this process depends largely on Ca(2+) entry through VDCCs and not Ca(2+) release through RyRs. These results indicate that Ca(2+) entry through VDCCs activates both BK and SK channels, but Ca(2+) release (Ca(2+) sparks) through RyRs activates only BK channels.

Algorithms↗
PubMed2002

Sarcoplasmic reticulum and membrane currents.

Local and global Ca2+ signals from voltage-dependent Ca2+ channels (VDCCs) and ryanodine-sensitive Ca2+ release (RyRs) channels in the sarcoplasmic reticulum (SR) encode information to different Ca2+-sensitive targets including the large- (BK) and small-conductance (SK) Ca2+-activated K+ channels in the surface membrane. In smooth muscle, unlike cardiac muscle, Ca2+ signalling to RyRs is not local, exhibiting a significant lag between VDCC activation and subsequent RyR stimulation, measured as Ca2+ sparks and associated BK currents. However, Ca2+ signalling from RyRs (Ca2+ sparks) to BK channels appears to be local in arterial (ASM) and urinary bladder smooth muscle (UBSM), consistent with a close proximity of SR RyRs to BK channels. The response of BK channels in ASM and UBSM depends on the tuning of the Ca2+/voltage sensitivity of the BK channel by its accessory subunit, the beta1 subunit. UBSM, in contrast to ASM, has both BK and SK channels. SK channels in UBSM are solely activated by Ca2+ signals from VDCCs, whereas BK channels are activated by Ca2+ from both VDCCs and RyRs. The differential regulation of BK and SK channels by Ca2+ signals underlies their roles in regulating action potential duration and membrane potential (BK channels) and after-hyperpolarizations (SK channels) in smooth muscle.

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