Emeritus Professor Alan North FRS, University of Manchester, UK
P2X and P2Y receptors were distinguished by Burnstock & Kennedy (1985) on the basis of differential actions of ATP analogs, notably ab-methylene-ATP and 2-methythio-ATP. P2Y receptors were involved in relaxation of intestinal smooth muscle, whereas P2X receptors were responsible for contraction of smooth muscle of the bladder and vas deferens. The eight P2Y receptors (numbered 1, 2, 4, 6, 11, 12, 13 and 14) are class A G-protein coupled receptors activated by ATP, ADP or UTP.
P2X receptors are trimeric membrane proteins that form cation channels activated by ATP. The seven P2X receptor genes in mammals encode proteins with intracellular N- and C-termini, and two membrane spanning domains separated by a large extracellular domain: channels form as homomers (numbered 1, 2, 3, 4, 5, 7) or heteromers (2/3, 1/5). In overall topology and subunit assembly, P2X receptors resemble acid-sensing ion channels (ASIC) and epithelial sodium channels (ENaC)(Browne et al. 2010; Baconguis et al 2013). The structures of the closed and open zebrafish P2X4 receptor (at 2.9 A: Hattori & Gouaux, 2012) are completely consistent with previous studies based on functional expression and site-directed mutagenesis (Browne et al 2010). They are also supported by more recent work using disulfide locking (Stelmashenko et al. 2014), gating by lipohilic attachment (Rothwell et al 2014) and gating by light using an attached bis(maleimido)azobenzene (Browne et al 2014).
The glymphatic system
Professor Maiken Nedergaard, Københavns University, Denmark
We have recently described a macroscopic pathway in the central nervous system – the glymphatic system that facilitates the clearance of interstitial waste products from neuronal metabolism. Glymphatic clearance of macromolecules is driven by cerebrospinal fluid (CSF) that flows in along para-arterial spaces and through the brain parenchyma via support from astroglial aquaporin-4 water channels. The glymphatic circulation constitutes a complete anatomical pathway; para-arterial CSF exchanges with the interstitial fluid, solutes collect along para-venous spaces, then drain into the vessels of the lymphatic system for ultimate excretion from the kidney or degradation in the liver. As such, the glymphatic system represents a novel and unexplored target for prevention and treatment of neurodegenerative diseases.
Calcium-dependent memory traces in neurons and glia
Professor Arthur Konnerth, Technische Universitaet Muenchen, Germany
The accumulation of amyloid-beta in the brain is an essential feature of Alzheimer’s disease (AD). However, the impact of amyloid-beta-accumulation on the dysfunction of neurons and circuits in vivo is still poorly understood. The neurodegeneration observed in AD has been initially associated with a progressive decrease in neuronal activity. Instead, in a mouse model of amyloidosis, we demonstrated that a substantial fraction of cortical neurons exhibit a massive increase in neuronal activity. These “hyperactive” neurons were located predominantly near the plaques of amyloid beta (Abeta)-depositing mice. In the visual cortex of the same mouse model, we found a progressive deterioration of sensory integration that paralleled the age-dependent increase of the amyloid-beta load. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons before the formation of plaques, suggesting that soluble species of Abeta may underlie the impaired neuronal activity. In support of this model, we found that the acute treatment of transgenic mice with a gamma-secretase inhibitor reduced soluble Abeta levels and rescued the neuronal dysfunction. Recently, we discovered an Abeta-dependent impairment of slow-wave propagation, which causes a breakdown of the characteristic long-range coherence of slow-wave activity in the mammalian brain. We demonstrated that this impairment can be rescued by enhancing GABAAergic inhibition and, thereby, reducing the level of hyperactivity. Together, our results support the notion that neuronal hyperactivity is a major cellular mechanism underlying circuit dysfunction in AD.
Regulation of neuronal calcium channel trafficking, subcellular localisation and function by auxiliary subunits
Professor Annette C Dolphin FRS, University College London, UK
Voltage-gated calcium channels are essential for the function of all excitable cells, since they link changes in excitation to entry of Ca2+ into the cells. The effects of Ca2+ in neurons include neurotransmitter release, and changes in gene expression. The CaV2 family of calcium channels mediate neurotransmitter release and are strongly expressed in presynaptic terminals. I will address the interplay between the function of neuronal calcium channels and the role of their auxiliary subunits, particularly α2δ, in excitable cells, and describe what happens when the channels undergo aberrant trafficking. There is increasing evidence that voltage-gated calcium channel dysfunction is involved in a number of disorders, including the development of chronic pain, a major source of morbidity in the population. In experimental models of chronic neuropathic pain, in which the peripheral axons of sensory dorsal root ganglion neurons are damaged, the auxiliary α2δ-1 subunit is upregulated strongly in the damaged neurons. In my presentation, I will discuss the role of the auxiliary α2δ subunits in calcium channel trafficking and function, in both cell lines and in neurons from wild-type and α2δ-1 knockout mice. I will also relate this to changes in channel distribution that occur in neuropathic pain.