Research

Thesis title: "Development of pharmacotherapies for GIRK linked diseases"

Thesis outline: Inward-rectifier potassium channels (Kirs) are lipid-gated ion channels that, in contrast with most K+ channels, allow K+ ions to flow more easily into the cell than out of the cell. They are present in both excitable and non-excitable membranes, and assume diverse physiological roles depending on the channel subtype and location. GIRK channels (Kir3; inwardly rectifying G protein activated K+ channels) underlie the inhibitory effects of major Gi/o coupled neurotransmitters in the heart, glands and brain and regulate heartbeat, aldosterone secretion, and neuronal excitability and plasticity.

GIRK channels are involved in pathophysiologies such as drug and alcohol addiction, pain, depression, seizures, and cognitive impairment in Down syndrome and Alzheimer’s Disease. Two neurological diseases linked to GIRK: Keppen-Lubinsky syndrome (KPLBS) caused by mutations in GIRK2 and GNB1 encephalopathy (GNB1E) caused by point mutations in the GNB1 gene that encode the Gb1 subunit of G proteins that regulate GIRK channels.

KPLBS is a rare and poorly understood disease first described in 2001. Presently, six de novo heterozygous mutations in KCNJ6 have been identified mainly in and close to the selectivity filter region (SF).

GNB1E is a new and poorly understood disease with no cure. It was first described in 2016 and is caused by >30 germline mutations found in the GNB1 gene. The ~100 cases documented so far present with global developmental delay, motor disorders, and frequently absence epilepsy or seizures. The actual number of affected patients is unknown and probably much higher.

Due to the specificity of diseases associated with GIRK channels (KPLBS, GNB1E), it is useful to use molecular dynamics in conjunction with other theoretical approaches. Theoretical calculations should allow us to evaluate the mechanisms of the influence of mutations on the structures and functions of GIRK channels, which will allow to develop ways to treat these diseases.

Funding: University Assistant (predoctoral)

Supervisor: Anna Weinzinger, Advisor: Nathan Dascal (Tel Aviv University, Israel)

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