抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Voltage-gated calcium channels are required for many key functions in the body. In this review, the different subtypes of voltage-gated calcium channels are described and their physiologic roles and pharmacology are outlined. We describe the current uses of drugs interacting with the different calcium channel subtypes and subunits, as well as specific areas in which there is strong potential for future drug development. Current therapeutic agents include drugs targeting L-type Ca(V)1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Ca(V)3) channels are a target of ethosuximide, widely used in absence epilepsy. The auxiliary subunit α2δ-1 is the therapeutic target of the gabapentinoid drugs, which are of value in certain epilepsies and chronic neuropathic pain. The limited use of intrathecal ziconotide, a peptide blocker of N-type (Ca(V)2.2) calcium channels, as a treatment of intractable pain, gives an indication that these channels represent excellent drug targets for various pain conditions. We describe how selectivity for different subtypes of calcium channels (e.g., Ca(V)1.2 and Ca(V)1.3 L-type channels) may be achieved in the future by exploiting differences between channel isoforms in terms of sequence and biophysical properties, variation in splicing in different target tissues, and differences in the properties of the target tissues themselves in terms of membrane potential or firing frequency. Thus, use-dependent blockers of the different isoforms could selectively block calcium channels in particular pathologies, such as nociceptive neurons in pain states or in epileptic brain circuits. Of important future potential are selective Ca(V)1.3 blockers for neuropsychiatric diseases, neuroprotection in Parkinson's disease, and resistant hypertension. In addition, selective or nonselective T-type channel blockers are considered potential therapeutic targets in epilepsy, pain, obesity, sleep, and anxiety. Use-dependent N-type calcium channel blockers are likely to be of therapeutic use in chronic pain conditions. Thus, more selective calcium channel blockers hold promise for therapeutic intervention.

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

The cerebellum and neural control

Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction

Neurons are generally considered to communicate information by increasing or decreasing their firing rate. However, in principle, they could in addition convey messages by using specific spatiotemporal patterns of spiking activities and silent intervals. Here, we review expanding lines of evidence that such spatiotemporal coding occurs in the cerebellum, and that the olivocerebellar system is optimally designed to generate and employ precise patterns of complex spikes and simple spikes during the acquisition and consolidation of motor skills. These spatiotemporal patterns may complement rate coding, thus enabling precise control of motor and cognitive processing at a high spatiotemporal resolution by fine-tuning sensorimotor integration and coordination.

Spatiotemporal firing patterns in the cerebellum

Kv4 low voltage-activated A-type potassium channels are widely expressed in excitable cells, where they control action potential firing, dendritic activity and synaptic integration. Kv4 channels exist as a complex that includes K(+) channel-interacting proteins (KChIPs), which contain calcium-binding domains and therefore have the potential to confer calcium dependence on the Kv4 channel. We found that T-type calcium channels and Kv4 channels form a signaling complex in rat that efficiently couples calcium influx to KChIP3 to modulate Kv4 function. This interaction was critical for allowing Kv4 channels to function in the subthreshold membrane potential range to regulate neuronal firing properties. The widespread expression of these channels and accessory proteins indicates that the Cav3-Kv4 signaling complex is important for the function of a wide range of electrically excitable cells.

https://people.ucalgary.ca/~rwturner/files/anderson_natneurosci_10.pdf

Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes

Encoding sensory input requires the expression of postsynaptic ion channels to transform key features of afferent input to an appropriate pattern of spike output. Although Ca2+-activated K+ channels are known to control spike frequency in central neurons, Ca2+-activated K+ channels of intermediate conductance (KCa3.1) are believed to be restricted to peripheral neurons. We now report that cerebellar Purkinje cells express KCa3.1 channels, as evidenced through single-cell RT-PCR, immunocytochemistry, pharmacology, and single-channel recordings. Furthermore, KCa3.1 channels coimmunoprecipitate and interact with low voltage-activated Cav3.2 Ca2+ channels at the nanodomain level to support a previously undescribed transient voltage- and Ca2+-dependent current. As a result, subthreshold parallel fiber excitatory postsynaptic potentials (EPSPs) activate Cav3 Ca2+ influx to trigger a KCa3.1-mediated regulation of the EPSP and subsequent after-hyperpolarization. The Cav3-KCa3.1 complex provides powerful control over temporal summation of EPSPs, effectively suppressing low frequencies of parallel fiber input. KCa3.1 channels thus contribute to a high-pass filter that allows Purkinje cells to respond preferentially to high-frequency parallel fiber bursts characteristic of sensory input.

https://www.pnas.org/content/pnas/109/7/2601.full.pdf

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

The ability for neurons to generate rebound bursts following inhibitory synaptic input relies on ion channels that respond in a unique fashion to hyperpolarization. Inward currents provided by T-type calcium channels (I(T)) and hyperpolarization-activated HCN channels (I(H)) increase in availability upon hyperpolarization, allowing for a rebound depolarization after a period of inhibition. Although rebound responses have long been recognized in deep cerebellar nuclear (DCN) neurons, the actual extent to which I(T) and I(H) contribute to rebound spike output following physiological levels of membrane hyperpolarization has not been clearly established. The current study used recordings and simulations of large diameter cells of the in vitro rat DCN slice preparation to define the roles for I(T) and I(H) in a rebound response. We find that physiological levels of hyperpolarization make only small proportions of the total I(T) and I(H) available, but that these are sufficient to make substantial contributions to a rebound response. At least 50% of the early phase of the rebound spike frequency increase is generated by an I(T)-mediated depolarization. An additional frequency increase is provided by I(H) in reducing the time constant and thus the extent of I(T) inactivation as the membrane returns from a hyperpolarized state to the resting level. An I(H)-mediated depolarization creates an inverse voltage-first spike latency relationship and produces a 35% increase in the precision of the first spike latency of a rebound. I(T) and I(H) can thus be activated by physiologically relevant stimuli and have distinct roles in the frequency, timing and precision of rebound responses.

https://people.ucalgary.ca/~rwturner/files/engbers_j_physiol_2011.pdf

Distinct roles for IT and IH in controlling the frequency and timing of rebound spike responses

Large diameter cells in rat deep cerebellar nuclei (DCN) can be distinguished according to the generation of a transient or weak rebound burst and the expression of T-type Ca2+ channel isoforms. We...

https://people.ucalgary.ca/~rwturner/files/molineux_dcn_bursts_08.pdf

Ionic Factors Governing Rebound Burst Phenotype in Rat Deep Cerebellar Neurons

Neurons of the deep cerebellar nuclei (DCN) play a critical role in defining the output of cerebellum in the course of encoding Purkinje cell inhibitory inputs. The earliest work performed with in vitro preparations established that DCN cells have the capacity to translate membrane hyperpolarizations into a rebound increase in firing frequency. The primary means of distinguishing between DCN neurons has been according to cell size and transmitter phenotype, but in some cases, differences in the firing properties of DCN cells maintained in vitro have been reported. In particular, it was shown that large diameter cells in the rat DCN exhibit two phenotypes of rebound discharge in vitro that may eventually help define their functional roles in cerebellar output. A transient burst and weak burst phenotype can be distinguished based on the frequency and pattern of rebound discharge immediately following a hyperpolarizing stimulus. Work to date indicates that the difference in excitability arises from at least the degree of activation of T-type Ca2+ current during the immediate phase of rebound firing and Ca2+-dependent K+ channels that underlie afterhyperpolarizations. Both phenotypes can be detected following stimulation of Purkinje cell inhibitory inputs under conditions that preserve resting membrane potential and natural ionic gradients. In this paper, we review the evidence supporting the existence of different rebound phenotypes in DCN cells and the ion channel expression patterns that underlie their generation.

/pdf/rebound-discharge-in-deep-cerebellar-nuclear-neurons-in-45pd1w7on2.pdf

Dustin Anderson

Papers

Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

Distinct roles for IT and IH in controlling the frequency and timing of rebound spike responses

Ionic Factors Governing Rebound Burst Phenotype in Rat Deep Cerebellar Neurons

Rebound Discharge in Deep Cerebellar Nuclear Neurons In Vitro