The Center for Molecular Neurobiology Hamburg (ZMNH), founded in 1988, is an internationally recognized molecular neuroscience research center, part of the University Medical Center Hamburg-Eppendorf (UKE), Germany. Headed by Matthias Kneussel, the ZMNH is currently home to 190 scientists and staff from 20 different countries (2024).
The focus of the ZMNH is basic research in neurobiology and neuroimmunology, combining molecular genetics with anatomical, biochemical and physiological approaches. The ZMNH is structured into six departments and several independent research groups.
Departments/Institutes
Independent Research Groups
Guest Groups
Research is supported by in-house facilities for bioanalytics, morphology and ultrastructure, transgenic animals, machine shop, IT department, and administration
Several proteins that are key to synaptic function were first cloned and characterized at the ZMNH, for example the presynaptic proteins Piccolo (PCLO) and Bassoon and the major organizer of the postsynaptic density, PSD-95 (a.k.a. SAP90). [1] [2] Synaptic activity controls the activity of certain genes, the so-called immediate early genes. Arg3.1/Arc, a prominent example of this gene family, was discovered at the ZMNH and found to have important functions in learning and memory. [3] [4]
An early focus of the center was understanding the structure and function of ion channels. The famous 'ball-and-chain' mechanism of potassium channel inactivation was discovered at the ZMNH. [5] A number of human diseases (hereditary forms of myotonia, osteopetrosis, retinal degeneration, kidney stone diseases, epilepsy, deafness) could be mapped to mutations in specific ion channels. [6] [7] [8] [9] These fundamental insights allowed researchers to mimic important aspects of human diseases in genetically accurate animal models, a key step in the development of new drugs. [10]
More recently, ZMNH researchers developed novel genetic tools to control neuronal activity with light (optogenetics), including the first light-gated chloride channel ChloC and the light-activated potassium channel PACK. [11]
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.
Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.
Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.
Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.
Channelopathies are a group of diseases caused by the dysfunction of ion channel subunits or their interacting proteins. These diseases can be inherited or acquired by other disorders, drugs, or toxins. Mutations in genes encoding ion channels, which impair channel function, are the most common cause of channelopathies. There are more than 400 genes that encode ion channels, found in all human cell types and are involved in almost all physiological processes. Each type of channel is a multimeric complex of subunits encoded by a number of genes. Depending where the mutation occurs it may affect the gating, conductance, ion selectivity, or signal transduction of the channel.
The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.
Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles. It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder, severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.
Sodium channel protein type 4 subunit alpha is a protein that in humans is encoded by the SCN4A gene.
Ca2+
/calmodulin-dependent protein kinase II is a serine/threonine-specific protein kinase that is regulated by the Ca2+
/calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for Ca2+
homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation.
Kv7.2 (KvLQT2) is a voltage- and lipid-gated potassium channel protein coded for by the gene KCNQ2.
PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene.
Syntaxin-1A is a protein that in humans is encoded by the STX1A gene.
Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the SAP97 gene.
The CLCN family of voltage-dependent chloride channel genes comprises nine members which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen).
The CLCN5 gene encodes the chloride channel Cl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of albumin and low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells. Mutations in the CLCN5 gene cause an X-linked recessive nephropathy named Dent disease characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis and nephrolithiasis.
Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.
Syntaxins are a family of membrane integrated Q-SNARE proteins participating in exocytosis.
In electrophysiology, the term gating refers to the opening (activation) or closing of ion channels. This change in conformation is a response to changes in transmembrane voltage.
Harald Jockusch is a German biologist and artist with the alias Hal Jos.
53°35′12″N9°58′16″E / 53.586671°N 9.97108°E
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