Biomedical subjects

Michael A Clark

Publications and source records attributed to Michael A Clark.

5 recordsLinked to original sources

PubMed2005

Endogenous regulator of G-protein signaling proteins regulate the kinetics of Galphaq/11-mediated modulation of ion channels in central nervous system neurons.

Slow synaptic potentials are generated when metabotropic G-protein-coupled receptors activate heterotrimeric G-proteins, which in turn modulate ion channels. Many neurons generate excitatory postsynaptic potentials mediated by G-proteins of the Galphaq/11 family, which in turn activate phospholipase C-beta. Accessory GTPase-activating proteins (GAPs) are thought to be required to accelerate GTP hydrolysis and rapidly turn off G-proteins, but the involvement of GAPs in neuronal Galphaq/11 signaling has not been examined. Here, we show that regulator of G-protein signaling (RGS) proteins provide necessary GAP activity at neuronal Galphaq/11 subunits. We reconstituted inhibition of native 2-pore domain potassium channels in cerebellar granule neurons by expressing chimeric Galpha subunits that are activated by Galphai/o-coupled receptors, thus bypassing endogenous Galphaq/11 subunits. RGS-insensitive variants of these chimeras mediated inhibition of potassium channels that developed and recovered more slowly than inhibition mediated by RGS-sensitive (wild-type) chimeras or native Galphaq/11 subunits. These changes were not accompanied by a change in agonist sensitivity, as might be expected if RGS proteins acted primarily as effector antagonists. The slowed recovery from potassium channel inhibition was largely reversed by an additional mutation that mimics the RGS-bound state. These results suggest that endogenous RGS proteins regulate the kinetics of rapid Galphaq/11-mediated signals in central nervous system neurons by providing GAP activity.

Animals↗

PubMed2004

Endogenous RGS proteins regulate presynaptic and postsynaptic function: functional expression of RGS-insensitive Galpha subunits in central nervous system neurons.

Regulators of G-protein signaling (RGS)-insensitive (RGSi) G-protein alpha subunits can be used to indirectly determine the function of endogenous RGS proteins in native cells. This article describes the application of RGSi Galpha subunits to the study of endogenous RGS function in central nervous system (CNS) neurons. Presynaptic inhibition of neurotransmitter release was reconstituted in primary neurons using RGSi Galpha(i/o) subunits, whereas postsynaptic regulation of potassium channels was reconstituted using RGSi chimeras of Galpha(q) and Galpha(i). These studies have shown that endogenous RGS proteins are essential for the rapid termination of some G-protein-mediated signals in CNS neurons, whereas these proteins are much less important for the regulation of other signals. Together, these techniques have helped reveal the complexity of RGS regulation of CNS function.

Adenoviridae↗

PubMed2003

Dopamine receptor agonists differ in their actions on cardiac ion channels.

Four dopamine receptor agonists used for the treatment of Parkinson's disease (apomorphine, pergolide, ropinirole and sumanirole) were evaluated for the ability to block human ether-a-go-go related gene (hERG) K(+) channels and to modify the duration of canine Purkinje fiber action potentials. Apomorphine, pergolide and ropinirole blocked the hERG-mediated currents with IC(50) values of 2.4, 0.12 and 1.2 microM, respectively. When evaluated in an action potential duration assay, pergolide significantly shortened action potential duration at 90% repolarization (APD(90)) whereas apomorphine and ropinirole significantly prolonged repolarization. Sumanirole only partially blocked hERG K(+) channels at the highest tested concentration (10 microM) and did not modify action potential duration over the tested concentration range (0.65-65 microM). Taken together, these data provide evidence that dopamine receptor agonists developed for the treatment of Parkinson's disease differentially influence hERG K(+) channel function and cardiac action potential duration.

Action Potentials↗

PubMed2003

Catastrophic desert formation in Daisyworld.

Feedback between life and its environment is ubiquitous but the strength of coupling and its global implications remain hotly debated. Abrupt changes in the abundance of life for small changes in forcing provide one indicator of regulation, for example, when vegetation-climate feedback collapses in the formation of a desert. Here we use a two-dimensional "Daisyworld" model with curvature to show that catastrophic collapse of life under gradual forcing provides a testable indicator of environmental feedback. When solar luminosity increases to a critical value, a desert forms across a wide band of the planet. The scale of collapse depends on the strength of feedback. The efficiency of temperature regulation is limited by mutation rate in an analogous manner to the limitation of adaptive fitness in evolutionary theories. The final state of the system emerging from single-site rules can be described by two global quantities: optimization of temperature regulation and maximization of diversity, which are mathematically analogous to energy and entropy in thermodynamics.

Adaptation, Physiological↗

PubMed2002

Factors affecting levels of physical activity in adults.

A large proportion of adults in Western cultures are physically inactive, despite several decades of warnings about the potentially negative health consequences of a sedentary lifestyle. Efforts to promote physical activity have focused on identifying its determinants and designing interventions that might effectively promote regular physical activity. The multitude of factors that induce adults to initiate and maintain programmes of physical activity have been divided into those that are invariable (age, gender, race, ethnicity) and those that are presumed to be modifiable (behavioural and personality characteristics, environmental circumstances and community settings). The lack of consistency in the design, analysis and reporting of interventions in the lives of inactive or sedentary individuals has produced equivocal results. However, several social and environmental factors have systematically emerged as determinants of physical activity in adults. In ethnic minorities, the removal of barriers such as unaffordable facilities and unavailable childcare, high crime rates, fear for personal safety and culturally inappropriate activities are of primary importance. Social support from family, peers, communities and healthcare providers has resulted in modest improvements across cultures, ages and genders in selected settings, but the definition of specific interventions and their outcomes deserve additional attention. Longitudinal studies indicate that components of physical fitness are relatively transitory, with low to modest correlations between physical activity and measures of physical fitness in childhood and adolescence and in adulthood. Attempts to explain the activity behaviour of adults by applying various theories in programmes of intervention have also produced mixed results. Successful interventions tailor programmes to individual needs, account for personal levels of fitness, allow for personal control of the activity and its outcomes, and provide for social support by family, peers and communities. The initiation and maintenance of regular physical activity in adults depends on a multitude of biological and sociocultural variables that demand attention across the lifespan.

Adult↗